Bispecific dual payload (2by2) ADCs combine the advantages of more specific and efficient payload delivery enabled by dual targeting with the ability to overcome drug resistance through the synergistic effect of dual payload design. Dual targeting enhances specificity by selecting co-expressed targets and balancing the binding affinity to each. Optimization of dual targeting can significantly increase internalization, translating to more efficient payload delivery to tumor cells. By incorporating two payloads with distinct mechanisms of action (MOA) on a single branched linker, 2by2 ADCs can simultaneously deliver both payloads to cancer cells. This simultaneous delivery has been shown preclinically to produce synergistic efficacy while maintaining manageable toxicity. The branched linker design also enables straightforward, one-step conjugation of dual payloads (DLPs) using thiol–maleimide chemistry.