The requirements for a cell surface molecule to be suitable as an antibody-drug conjugate target are stringent. The notion that antibodies-directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody-drug conjugates has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that were either not sufficiently potent, were immunogenic (proteins) or were too toxic and linkers that were not sufficiently stable in circulation. Three main avenues have been explored using antibodies to target cytotoxic species to malignant cells, antibody-protein toxin conjugates (or antibody fragment-protein toxin fusion proteins), antibody-small molecule drug conjugates and antibody-enzyme conjugates administered along with small molecule prodrugs requiring metabolism by the conjugated enzyme to release the activate species. This review focuses on cell surface proteins that have been targeted primarily by antibody-small molecule drug conjugates and briefly discusses 34 targets being investigated. While only one antibody-drug conjugate has reached regulatory approval, there are nearly 20 of these in clinical trial. The time may have come for this technology to become a major contributor to improving treatment for cancer patients.