Plant diseases account for 15% of crop loses worldwide, presenting a significant economic, environmental and social challenge in a world facing increased demands on food, fibre and biofuels. Key determinants of plant disease resistance or susceptibility are the disease-causing molecules from pathogens, known as effectors, and the aptly named plant disease resistance genes. Plant resistance genes often encode proteins with nucleotide-binding, leucine-rich repeat domains that structurally and functionally resemble mammalian nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) protein, which are also involved in immunity. NLR proteins enable plants to detect specific pathogen effectors from the repertoire of effector molecules that pathogens secrete during infection. We are combining structural biology, protein biophysics and biochemistry with in planta functional experiments to understand how NLR proteins function. Here I will describe our major advancements in this area, with a focus on the N-terminal signaling domains and paired NLR protein receptors. The broader implications of these results and future challenges will also be discussed.