Complex series of defense response activation, consistent with the studies conducted in the model plant Arabidopsis thaliana, has been demonstrated in tomato during incompatible pathogen/pest interactions. During the past two decades, numerous tomato genes have been identified conferring resistance to diverse pathogens/ pests in a gene-for-gene manner. A few of these cloned resistance (R)-genes (Cf and Pto) have been extensively studied and excellent existing reviews describe R-gene function, interacting proteins and the mechanism of Avirulence effector perception. Recent comprehensive gene expression analysis of tomato responses to biotic stresses resulted in identification of genes and potential molecular processes that are associated with several of the tomato R-genemediated resistance responses. The purpose of this review is to provide an overview of tomato R-gene-mediated defense responses to different pathogens/pests together with the components involved in the organization of this highly complex network of plant defenses. Global transcriptome profiling is an important initial step for dissecting biological systems particularly with systems where not much is known about the molecular basis of the resistance response. The enrichment of the tomato EST databases initiated several genomewide profiling studies [32][33][34][35]. This facilitated significant progress in the characterization of tomato incompatible responses to Avr pathogens, contributing to future gene identification and to the understanding of the potential molecular processes that are associated with the different tomato R-gene-mediated resistances [33]. With the advent of next generation sequencing technologies, and the tomato genome sequence [36], additional genome wide studies have been conducted. With a genome sequence and a high-density linkage and molecular maps [37], combined with being a host for numerous pathogens and pests, tomato has emerged as a powerful model system for crop plant defense response studies. Moreover, the introgression of R-genes from wild species into cultivated tomato provides a unique opportunity to study different resistance mechanisms against very diverse biotic agents in a single plant. In this review, we summarize the current understanding of R-genes in tomato and the downstream signaling components that are critical for activating defense responses. In addition, we discuss the current and future technologies that will significantly enhance our knowledge about tomato-pathogen interactions and will provide alternative strategies to develop a sustainable resistance. Tomato Resistance Genes and their Modes of ActionHost resistance is an important component of a sustainable disease management system [38]. It is an environmentally benign method that can be used as an alternative to chemicals, as their applicability against Verticillium. The Ve locus contains two closely linked and inversely oriented genes, Ve1 and Ve2, both encoding a RLP-type cell surface receptor. Ve1 R-gene provides resistance against ra...