Comparative oncology clinical trials are a growing part of the cancer research armamentarium. In these trials, biologically rich data are collected in pet dogs that have naturally developed cancers in their lifetimes, in the context of intact, educated immune systems and comparable environmental exposures to their human companions. The data generated can inform on a drug’s efficacy and tolerability and provide key insights into pharmacodynamic/dynamic relationships through longitudinal clinical observations and biologic sample collections. The organization and execution of comparative oncology trials are foundationally built upon careful consideration of questions rooted in cancer biology and drug development that cannot be sufficiently asked or answered in other model systems. Equally important is attention to species-specific assay support to aid in the interpretation of trial results. This chapter educates the reader by discussing the key concepts relating to the logistical aspects and execution of comparative oncology clinical trials to enhance translational and technical success.