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Almost 48 years after the gene-for-gene interaction model was proposed by Flor, NBS-LRR resistance (R) genes are still the focus of intense research interest. Also called NB-LRR, NB-ARC, NLR (Nucleotide Binding Domain and Leucine-rich Repeat), this group regards the largest R gene class, accounting for more than half of the plant R genes, with an impressing number and structural diversity, especially in angiosperms. With the omics advent, especially genomics and transcriptomics, an emergence of the so-called NLRomics came out, allowing the annotation and comparative analysis of NBS-LRR members at functional and structural level on a previously unfeasible scale. The present chapter provides a retrospective of studies involving NBS-LRR genes and proteins, including information on mechanisms of action, regulation, patterns of expression, subcellular localization, origin, diversification, and evolution in plants. Aspects of plant-pathogen coevolution are discussed, as well as resistance-breaking mechanisms reported in the literature. Main databases compiling NBS-LRR genes are discussed, and a routine for their annotation and structural analysis is presented. Practical implications of NBS-LRR molecules are considered, together with aspects about existing limitations and their potential biotechnological applications.