The U.S. Food and Drug Administration recently issued an Exploratory Investigational New Drug (IND) guidance that provides a platform for the evaluation of targeted anticancer agents in small, early-phase human clinical trials that can be used to establish the feasibility of proof-of-principle target modulation assays, as well as the preliminary pharmacokinetics and molecular imaging potential of new anticancer molecules. The exploratory IND allows for reduced requirements for manufacturing and toxicologic assessment. Early clinical trials done in this fashion have no therapeutic intent. In this series of articles in CCR Focus, the development of this new IND mechanism, its effect on clinical trial design and clinical pharmacodynamics, the ethical implications of nontherapeutic clinical investigations, and the perspective of the pharmaceutical industry on this approach are examined.