Defense response by NBS-LRR proteins (NLRs) is a sophisticated strategy that induces effector-triggered immunity (ETI). The NBS-LRR proteins are encoded by one of the largest and most important gene families involved in disease resistance in plants. These NBS-LRR proteins are mainly intracellular, and they can specifically recognize effectors secreted by pathogens either directly or indirectly. This will trigger downstream signaling pathways leading to implementation of plant defense response against various classes of pathogens including bacterial, fungal, viral, nematode and insect. In the present chapter we discuss about the present knowledge pertaining to NBS-LRR class of proteins; their structural organization, genomic ditribution and evolution.