The complex nature of the pharmacologic aspects of cancer therapeutics has become more apparent in the past several years with the arrival of a cascade of target-based agents and the difficult challenge of bringing individualized precision medicine to oncology. Interpatient variability in drug action, singularly in novel agents, is in part caused by pharmacogenomic (PG), pharmacokinetic, and pharmacodynamic (PD) factors, and drug selection and dosing should take this into consideration to optimize the benefit for our patients in terms of antitumor activity and treatment tolerance. In this regard, somatic genetic evaluation of tumors is useful in not only predicting response to initial targeted therapies but also in anticipating and guiding therapy after the development of acquired resistance; therapeutic drug monitoring of novel small molecules and monoclonal antibodies must be incorporated in our day-to-day practice to minimize the negative effect on clinical outcome of interindividual variability on pharmacokinetic processes of these drugs for all patients, but especially for fragile patient populations and those with organ dysfunction or comorbidities. For these populations, incorporating frailty assessment tools into trials of newer agents and validating frailty-based dose adjustment should be an important part of further drug development.