Antibody-drug conjugates (ADCs) represent an emerging new paradigm in cancer therapy. The approval of two ADCs has spurred considerable interest in this area of research, and over 55 ADCs are currently in clinical testing. In order to improve the clinical success rate of ADC therapy, all three components of the ADC: the antibody, linker, and payload have to be optimized. While considerable improvements have been made in antibody properties and target selection, medicinal chemistry efforts have lagged behind, and there is a significant need for innovation in linker design and payloads.