Antibody–drug conjugates (ADCs) represent an increasing proportion of therapeutics in preclinical and clinical development for the treatment of oncology indications. ADC-based therapies are attractive due to their potential to increase efficacy and reduce the systemic toxicity produced by other conventional anticancer regimens. ADCs are complex molecules, however, and their clinical success depends both on the properties of the target in the context of the disease and on the properties of the ADC itself: the antibody, the toxin payload, and the linker, to which it is coupled, and the site and chemistry of linkage. In this chapter, we review some of the strategies that can be utilized to generate and characterize optimal ADC antibodies, including selection of appropriate targets, development of tools for antibody generation and screening, approaches to antibody isolation, advanced screening strategies for lead antibody selection, antibody engineering to increase selectivity and potency, and selection of appropriate combinations of linker, payload, and linker attachment strategy.