Diseases caused by an excess of protein function can often be treated by small molecule inhibitors. In contrast, many diseases caused by missing proteins cannot be addressed with this classic therapeutic strategy. Emerging evidence suggests that small molecules may further possess the capacity to autonomously replicate the functions of many missing proteins, thereby operating as prostheses on the molecular scale. A powerful new building block-based approach for small molecule synthesis is facilitating the systematic study of a variety of small molecules with protein-like functions and thereby brightening the prospects of realizing the substantial potential of this molecular prosthetics approach.