Cancer treatment is complicated because of a multitude of treatment options and little patient-specific information to help clinicians choose appropriate therapy. There are two genomes relevant in cancer treatment: the tumor (somatic) and the patient (germline). Together, these two genomes dictate treatment outcome through four processes: the somatic genome primarily determines tumor prognosis and response while the germline genome modulates treatment exposure and toxicity. In this review, we describe the influence of these genomes on treatment outcomes by highlighting examples of genetic variation that are predictors of each of these four factors, prognosis, response, toxicity and exposure, and discuss the translation and clinical implementation of each. Use of pre-treatment pharmacogenetic testing will someday enable clinicians to make individualized therapy decisions about aggressiveness, drug selection and dose, improving treatment outcomes for cancer patients.