In silico techniques are frequently adopted in drug discovery in order to assist with ligand design. Although relevant software and technologies are readily available, there are few examples in the literature of the use of molecular modelling techniques in the development of antibody–drug conjugate (ADC) payloads. This chapter summarises the in silico studies that have been carried out on the tubulin-binding monomethyl auristatin E and F (MMAE/MMAF) and DNA-interactive pyrrolobenzodiazepine (PBD) dimer payloads, the two best-known examples of the application of this approach. The PBD dimers are possibly the only example of a payload family where molecular modelling approaches have been extensively used for their discovery and development. Therefore, the main focus of the discussion is on how computational methods have led to a set of “rules” for the interaction of PBD dimers with DNA which can be used as a tool for the design of next-generation DNA-binding payloads.