Three related articles in this issue addressing clinical and translational (C/T) research suggest four simple questions about such research that should be considered by policy makers at a national level, by academic institutions, and by individual scientists: What, who, how, and why. The author of this commentary posits that ambiguity in answering these questions means that policy makers are not providing a clear target for institutions and researchers. The vagueness of the definitions may also obscure accountability with regard to assessing whether the rhetoric matches actions-for instance, what is the distribution of research activities and funding across the different phases of C/T research? Given the rapid evolution of new tools and methodologies in C/T research, it is important to consider each of these issues across the full developmental pathway of a C/T researcher. Overcoming these challenges and rapidly advancing along the pathway of creating knowledge to enhance the health of our communities and the nation depends on coherence and agreement by all players involved in C/T policy, funding, and participation.