The emergence of molecularly targeted agents in oncology has not only revolutionized the care of cancer patients, but also changed the daily practice of medical oncologists. Molecularly targeted agents indeed often differ from traditional cytotoxic agents by their administration schedules and routes, their toxicity profiles, and/or the assessment of their antitumor activity. In addition, the observation that molecularly targeted agents sometimes have limited antitumor activity as single agents has led clinical investigators to combine molecularly targeted agents together or with cytotoxic agents. We review here the current challenges for the early clinical development of anticancer agents in the era of molecularly targeted agents. We focus on the choice of end points in phase I oncology clinical trials, as well as on the choice of dose escalation methods with an emphasis on available dose escalation methods for molecularly targeted agents and for combination trials.