AbstractKiller immunoglobulin‐like receptors (KIRs) play an essential role in the regulation of natural killer (NK) activity, allowing NK cells to sense and respond to human leukocyte antigen (HLA) class I downregulation, an important hallmark for viral infections and tumor transformation. KIR and HLA genes are located on different chromosomes and KIR/HLA class I interaction represents an example of genetic epistasis in which the presence of receptor/ligand pairs is necessary for the induction of functional activity, while the presence of one in the absence of the other is not sufficient to influence NK cell function. Due to the high degree of HLA class I and KIR gene variability, KIR/KIR‐ligand (KIR‐L) interactions are extraordinarily diverse. KIR polymorphism arises from both haplotypic and allelic variations and was shaped by natural selection. KIR variability affects NK cell education influencing the KIR repertoire, KIR expression, the strength of KIR/KIR‐L interactions and the capability to deliver signals. Moreover, it may influence NK cell function during infections, autoimmune diseases, pregnancy and allogeneic transplantation. This review summarizes the genetic and functional features of KIR/KIR‐L interactions and gives an overview of their potential relevance in clinical studies.