The maximum tolerated dose (MTD) has been the classically recommended phase II dose for cytotoxic chemotherapy anticancer agents. However, the development of molecular targeted therapies with highly specific mechanisms of action has raised questions about the paradigm of dosing at the MTD. Inhibition of the molecular target may occur at dose levels substantially below those producing dose limiting toxicities. The impact of targeted therapies on our dose selection strategies has been immense; however, defining the MTD in phase I oncology trials still provides valuable information for future drug development. But, the MTD should not be selected blindly as the recommended phase II dose for efficacy testing. Optimal dose selection for targeted cancer agents needs to be evaluated using all available information collected during the early stages of drug development. Definition of the optimal dose may need to be deferred until randomized phase II trials can be conducted. Future clinical trail designs in oncology drug development need to reflect this paradigm shift.