KEY POINTS Several aspects of phase I trials have evolved in the current era of molecular targeted agents to adapt to the changing nature of anticancer therapy and to increase the efficiency of drug development. Current phase I designs are increasingly integrating novel dose-escalation approaches and biomarker-driven selection of patients, as well as expanding study objectives to include the evaluation of efficacy and pharmacodynamics/pharmacokinetics in addition to safety. Changes to the regulatory approval process have helped to expedite drug development, particularly for novel agents with a strong biologic rationale and proof of concept, validated predictive biomarker, and clear evidence of efficacy in early trials. As a result of the substantial changes in phase I trial goals and conduct, there is a parallel shift toward multi-institutional trials and central study management by clinical research organizations. The use of multi-institutional trials has a significant impact on the structure of phase I programs and the experience of investigators, particularly because of limited patient enrollment at each site.