Antibody–drug conjugates (ADCs) combine the high target specificity and favorable pharmacokinetics of monoclonal antibodies with the potent tumor-killing properties of cytotoxic agents and have demonstrated convincing antitumor effects in both animal models and patients. However, the inherent complexity of ADCs with their multiple components often makes their development challenging. Pharmacokinetic and ADME (absorption, distribution, metabolism, and excretion) characterization of ADCs reflects the dynamic interactions between the biological system and ADC and provides critical assessments in lead selection, optimization, and clinical development. A rational strategy integrating the mechanistic understanding of pharmacokinetics/pharmacodynamics and ADC disposition helps to inform target selection, drug selection, and linker design and ultimately to maximize the therapeutic window. In this chapter, we give an overview of ADC PKPD and disposition and discuss our current understanding of the major determinants, unique challenges, and lessons learned from the current ADC landscape. The utility of PKPD modeling is also discussed in the context of providing guidance to assist in the successful development of these complex molecules.