Selection of appropriate targets is likely the most important consideration for the success of an antibody-drug conjugate (ADC) development program. Target selection for ADCs can be classified into two principal approaches: target-first and antibody-first approach or agnostic approach (Fig. 3.1). In the target-first approach, a target is chosen based on a set of factors, including expression pattern, abundance and internalization properties, and an antibody-generation campaign is focused on isolation of antibodies against this target. In the agnostic approach, antibodies capable of binding to and internalizing in tumor cells are isolated, followed by retrospective identification of their targets. While the target-first approach may have the advantage of a higher degree confidence in the suitability and novelty of the target based on prior knowledge of target properties, it requires significant work before internalizing antibodies become available. By contrast, the agnostic approach leads quickly to reagents suitable for testing hypotheses directly, although this strategy tends to favor highly expressed surface antigens, which are likely to have been described previously.