Both in hematopoietic stem cell transplantation (HSCT) and in solid-organ transplantation (SOT), T and B cell-mediated immunity toward nonshared HLA alleles can have a detrimental outcome. In the past decade, many studies have investigated whether natural killer (NK) cell-mediated immunity might also play a role in clinical transplantation. This work has focused on killer cell immunoglobulin-like receptors (KIRs), as these NK cell receptors interact with HLA class I molecules in an allele-specific manner. In this chapter, we describe the genetics and functions of KIRs and discuss their role in HSCT and SOT.