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Antibody-drug conjugates (ADCs) have evolved in the last decade or two from carrying a single chemotherapy payload to carrying highly potent tubulin inhibitors and DNA damaging agents. While the latter have shown success in the clinic, efficacy has been constrained by therapeutic resistance, limited tumor penetration, and suboptimal immune activation. Currently, the ADC development space also includes the development of tumor-targeting monoclonal antibodies that carry dual-payloads, incorporating both cytotoxic agents and, for example, immunostimulatory molecules that could synergize direct tumor cell killing with reprogramming of the tumor immune microenvironment (TME). The translational and clinical pharmacology development strategy for ADCs is complicated by the need to understand the mechanism of action (MoA), the pharmacokinetics, and the pharmacodynamics of the different components of the ADC, and this gets even more complicated when two payloads are in play. The challenge lies, for instance, in understanding the MoA of each payload and the resulting synergy in effect, the increased number of analytes for bioanalysis, and the potential for added anti-drug antibody (ADA) formation due to more available epitopes in the ADC that could be recognized by the immune system. To date, no dual-payload ADCs have been approved, and this review is therefore intended to provide an overview on the translational science and clinical pharmacology strategies in the development of ADCs with two or more payloads based on what is currently known and published about single-payload ADCs and the authors' perspective.