Tuta absoluta is one of the most destructive pest affecting tomato crops, causing considerable field and greenhouse yield losses. Despite its economic importance, little is known about the molecular basis of the interaction between this leafminer and tomato plants. To investigate the tomato response to T. absoluta challenge , a multi-omic approach was carried out. Tolerant and Susceptible cultivated tomato genotypes as well as the derived F1 hybrid were employed to shed light on the plant response to the herbivore feeding. A RNA-Seq experiment was performed to analyze the transcriptional reprogramming of three tomato genotypes infested by T. absoluta. Metabolome fingerprinting analysis was carried out both to analyze differences in metabolites production among infested and not infested genotypes and to validate gene expression findings. Furthermore, a structural genomic-based analysis allowed us to identify polymorphisms such as SNPs and InDels affecting genes putatively involved in tomato-T. absoluta interaction. In the Tolerant genotype, the reprogramming driven by both direct and indirect defenses is based on an antixenosis mechanism. This is characterized by the lower utilization of the host by the herbivore due to chemicals, physical and morphological barriers. The RNA-Seq gene expression analysis allowed us to assess an active recognition of the insect that leads to a signaling cascade mediated by the systemin/jasmonic acid complex and, subsequently, the activation of genes involved in the growth of trichomes (physical barriers) together with the activation of genes coding for production of volatile terpenes and phenylpropanoids. A direct defense has been well elucidated by the metabolome analysis, revealing an involvement of compounds such as chlorogenic and neo-chlorogenic acids, GABA and, pyridinc alkaloid trigonelline. The susceptible line demonstrates to be less capable of deploying with the defense arsenal. The key genes identified in JA, terpenes and phenylpropanoids pathways resulted down-regulated and affected by deleterious variants that could lead to important changes in the final protein synthesis. The F1 derived from the cross between the Tolerant and Susceptible lines expresses, even if at less extent, the key genes identified in the tolerant line, and is affected by the same structural polymorphisms. Results obtained in this thesis suggest that the tolerance to the leafminer T. absoluta is modulated both by structural variations and by the expression regulation of such genes. The findings gathered in this study could be very useful for better direct future tomato breeding for T. absoluta tolerance