Plants have evolved several adaptive strategies through physiological changes in response to herbivore attacks. Plant secondary metabolites (PSMs) are synthesized to provide defensive functions and regulate defense signaling pathways to safeguard plants against herbivores. Herbivore injury initiates complex reactions which ultimately lead to synthesis and accumulation of PSMs. The biosynthesis of these metabolites is regulated by the interplay of signaling molecules comprising phytohormones. Plant volatile metabolites are released upon herbivore attack and are capable of directly inducing or priming hormonal defense signaling pathways. Secondary metabolites enable plants to quickly detect herbivore attacks and respond in a timely way in a rapidly changing scenario of pest and environment. Several studies have suggested that the potential for adaptation and/or resistance by insect herbivores to secondary metabolites is limited. These metabolites cause direct toxicity to insect pests, stimulate antixenosis mechanisms in plants to insect herbivores, and, by recruiting herbivore natural enemies, indirectly protect the plants. Herbivores adapt to secondary metabolites by the up/down regulation of sensory genes, and sequestration or detoxification of toxic metabolites. PSMs modulate multi-trophic interactions involving host plants, herbivores, natural enemies and pollinators. Although the role of secondary metabolites in plant-pollinator interplay has been little explored, several reports suggest that both plants and pollinators are mutually benefited. Molecular insights into the regulatory proteins and genes involved in the biosynthesis of secondary metabolites will pave the way for the metabolic engineering of biosynthetic pathway intermediates for improving plant tolerance to herbivores. This review throws light on the role of PSMs in modulating multi-trophic interactions, contributing to the knowledge of plant-herbivore interactions to enable their management in an ec These metabolites cause direct toxicity to insect pests, stimulate antixenosis mechanisms in plants to insect herbivores, and, by recruiting herbivore natural enemies, indirectly protect the plants. Herbivores adapt to secondary metabolites by the up/down regulation of sensory genes, and sequestration or detoxification of toxic metabolites. PSMs modulate multi-trophic interactions involving host plants, herbivores, natural enemies and pollinators. Although the role of secondary metabolites in plant-pollinator interplay has been little explored, several reports suggest that both plants and pollinators are mutually benefited. Phenolics can directly act as toxins to herbivores or can be oxidized by peroxidases or polyphenol oxidases to toxic metabolites which cause physiological disturbances in insect growth and These breakdown products of glucosinolates are as effective as synthetic insecticides [ 25 ] and have been shown to be extremely toxic to herbivorous insects and to repel them from feeding [ 26 ]. 2.4. Nitrogen-Containing Compounds Nitrogen-containing secondary metabolites include alkaloids. To date, around 10,000 different derivatives of alkaloids have been reported across the plant kingdom [ 27 ]. Alkaloids are divided into three groups on the basis of biosynthesis [ 28 ]: (a) true alkaloids (e.g., nicotine, morphine, quinine and atropine); (b) pseudo-alkaloids (e.g., capsaicin, solanidine and caffeine); and (c) proto-alkaloids (e.g., yohimbine, mescaline and hordenine). Effect of Plant Secondary Metabolites on the Physiology and Behavior of Herbivores Plants need to respond rapidly to herbivory and produce defense chemicals at the site of the attack. Secondary metabolites may repel or deter the feeding or cause direct toxic symptoms leading to inhibition of growth which ultimately results in the death of insects ( Figure 3 ). Recent molecular tools enable us to detect the target sites of these toxins at cellular or molecular level. Defense response of these PSM compounds is flexible which is modulated by herbivore damage [ 101 ]. Some of these metabolites are constitutive while others are generated after herbivore attacks. Introgression of 7-epi-zingiberene biosynthetic pathways in tomato cultivars enabled the plant to be less attractive to whitefly and toxic to spider mites ( Tetranychus urticae ) [ 119 ]. Recently, several studies have reported the effectiveness of PSMs against herbivores applied in an eco-friendly way ( Supplementary Table S1 ). 7. Adaptations of Herbivore Insects to Plant Secondary Metabolites The continuous adaptation of insect pests to plant defensive characters is responsible for the coexistence of insects. Insect herbivores adapt themselves to plant secondary metabolites by different strategies, including by detoxifying plant toxins, alteration of the toxic compounds into favorable compounds for their growth and development, developing the choice of feeding on the basis of secondary metabolite concentration, quick engrossment and expulsion as feces, and enlisting the aid of symbiotic intestinal microbes in order to mitigate the effect of toxic PSMs [ 10 , 120 ] ( Figure 4 ). Furthermore, herbivores also employ secondary metabolites as chemical indicators through their well-developed chemoreceptors. Toxic secondary metabolites are stored by insects, which are later utilized as protection against their natural enemies and to protect their eggs [ 120 ]. However, the innate ability of flora to produce chemicals in defense against insect attack should be fully exploited in order to improve the performance of secondary metabolites. Subduing the host defense response through use of secreted protein effectors is also one of the adaptive mechanisms in insects to PSMs [ 121 ]. Figure 4 Insect Counter Adaptation to Plant Secondary Metabolites. Several factors contribute to the successful adaptation of insect herbivores, one being insect robust olfactory systems and swift evolution [ 122 ].