Musk was originally identified in male musk deer and other mammals to mark territories and attract females. In humans, musk compounds are widely used in perfumes and consumer products for their superior perceptual odor quality. Strikingly diverse natural and synthetic chemicals have exhibited a similar "musky" odor, which has resulted in diverse models of musk odor perception and raises questions regarding the simplistic associations between chemical features and odor quality. Scientists' lack of understanding of this principle has hampered the design of a novel musk compound. Here, we functionally identified the odorant receptor, OR5A2, as a receptor for the musky odor of diverse musk compounds. First, we discovered that engineered OR5A2 with enhanced expression in heterologous cells is sensitive to and selective of musk compounds in all four structural classes. Second, the clarified functional variation of OR5A2 accounts for the reported association between genetic variation and perception in a musk compound. Finally, the revealed ligand selectivity of OR5A2 provides insight into developing a trained model to use machine learning-based virtual screening on candidates for a new musk compound. We propose that OR5A2 contributes to the long-sought gateway of sensing musk compounds and generating their unique odor quality.