NKG2D is a major stimulatory receptor expressed by natural killer (NK) cells and some T cells. The receptor recognizes major histocompatibility complex class I-like cell surface ligands that are poorly expressed by normal tissues but are often induced in transformed and infected cells. The existence of several NKG2D ligands in each individual, some with strikingly divergent protein sequences, raises the possibility that different ligands are regulated by distinct disease-associated stresses. The transcripts for some ligands, including murine UL16-binding proteinlike transcript 1 (Mult1), are abundant in certain normal tissues where cell surface expression is absent, suggesting the existence of translational or posttranslational regulation. We report here that under normal conditions, Mult1 protein undergoes ubiquitination dependent on lysines in its cytoplasmic tail and lysosomal degradation. Mult1 degradation and ubiquitination is reduced in response to stress imparted by heat shock or ultraviolet irradiation, but not by other forms of genotoxicity, providing a novel mechanism for stress-mediated cellular control of NKG2D ligand expression.