The homodimeric immunoreceptor NKG2D drives the activation of effector cells following engagement of diverse, conditionally expressed MHC class I-like protein ligands. NKG2D recognition is highly degenerate in that a single surface on receptor monomers binds pairs of distinct surfaces on each structurally divergent ligand, simultaneously accommodating multiple nonconservative ligand allelic or isoform substitutions. In contrast to TCR-pMHC and other NK receptor-ligand interactions, thermodynamic and kinetic analyses of four NKG2D-ligand pairs (MIC-A*001, MIC-B*005, ULBP1, and RAE-1beta) reported here show that the relative enthalpic and entropic terms, heat capacity, association rates, and activation energy barriers are comparable to typical, rigid protein-protein interactions. Rather than "induced-fit" binding, NKG2D degeneracy is achieved using distinct interaction mechanisms at each rigid interface.