Phase I trial design is constantly evolving to adapt to deficiencies in traditional methods and to accommodate newer rationally designed agents. This article discusses some of the important aspects of the design of phase I studies with particular reference to identifying new methods of safer but rapid dose escalation and reproducible end points such as maximum tolerated dose and recommended phase II dose. Given the explosion of rationally designed drugs capable of pathway specific inhibition, we also discuss potential strategies in designing trials with these agents. It is hoped that future strategies incorporate the existing methodologies with newer dose titration examples to complete phase I trials in a rapid and timely fashion.