The Ly49 and Nkrp1 loci encode structurally and functionally related cell surface proteins that positively or negatively regulate natural killer (NK) cell-mediated cytotoxicity and cytokine production. Yet despite their clear relatedness and genetic linkage within the NK gene complex (NKC), these two multi-gene families have adopted dissimilar evolutionary strategies. The Ly49 genes are extremely polymorphic and evolutionarily dynamic, with distinct gene numbers, remarkable allelic diversity, and varying MHC-I-ligand specificities and affinities among different murine haplotypes. In contrast, the Nkrp1 genes have opted for overall conservation of genomic organization, sequences, and ligand specificities, with only limited and focused allelic polymorphism. Possible selection pressures driving such varied evolution of the two gene families may include disequilibrium from ligand co-inheritance, pathogen immunoevasin strategies, flexibility in host counter-evolution mechanisms, and the prevalence and dynamics of inherent repetitive elements.