Creating antibody–drug conjugates (ADCs) by attaching cytotoxic effector molecules to antibodies that can selectively bind to targets on the surface of cancer cells is an approach for the selective delivery of cytotoxic agents to cancer cells while minimizing toxicity toward normal cells that lack the cell-surface target of the antibody. The successful application of this concept should yield ADCs that have a wider therapeutic index than that of small-molecule cytotoxic compounds (i.e. “classical” chemotherapy). Since the approvals of brentuximab vedotin in 2011 and ado-trastuzumab emtansine in 2013, two ADCs that contain potent tubulin-binding agents as their payloads, there has been an explosion of research in the field, with more than 65 ADC compounds in clinical evaluation at the end of 2017. In the last few years, medicinal chemists have generated a wide variety of cytotoxic compounds that kill cells by a variety of mechanisms, and that could serve as payloads for ADCs. The purpose of this chapter is to review the factors important for the design of ADCs, factors that medicinal chemists need to take into account when creating payloads and their linkers and when designing the payload-release mechanisms, all of which can influence the therapeutic effectiveness of ADCs in treating patients with cancer.