A new eye on NLR proteins: focused on clarity or diffused by complexity?

► We discuss recent advances in understanding animal and plant NLRs in a comparative fashion. ► P-loop-dependent and independent modes of activation are highlighted. ► We review evidence for homo- and hetero-dimerization requirements for NLR functions. ► We discuss unconventional functions for plant NLRs beyond pathogen effector recognition. ► We describe nuclear-cytoplasmic partitioning requirement for NLRs across the two kingdoms.