The study of plant diseases is almost as old as agriculture itself. Advancements in molecular biology have given us much more insight into the plant immune system and how it detects the many pathogens plants may encounter. Members of the primary family of plant resistance (R) proteins, NLRs, contain three distinct domains, and appear to use several different mechanisms to recognize pathogen effectors and trigger immunity. Understanding the molecular process of NLR recognition and activation has been greatly aided by advancements in structural studies, with ZAR1 recently becoming the first full-length NLR to be visualized. Genetic and biochemical analysis identified many critical components for NLR activation and homeostasis control. The increased study of helper NLRs has also provided insights into the downstream signaling pathways of NLRs. This review summarizes the progress in the last decades on plant NLR research, focusing on the mechanistic understanding that has been achieved.