This chapter outlines a stepwise approach to building clinical research careers in this arena of bedside-to-bench and back form of clinical investigation. For the purposes of this chapter, a relatively restricted definition will apply, referring specifically to that subset of human investigations that address the “first translational block.” This term refers to that form of clinical research that focuses on the increasingly dynamic interface between bedside and bench. Careers in translational research are uniquely challenging and rewarding. Continually updating technological tools, reeducating oneself across an entire career, juggling the conflicting mandates of teaching, patient care, and research, and repeatedly competing for peer-reviewed funding are not for the faint of heart. However, research at the translational interface represents one of the most deeply satisfying careers that exists in academic medicine. The leverage is vast and the ability to potentially contribute to the alleviation of human suffering is irresistibly attractive, making all of the challenges seemingly small compared to the opportunity to accomplish a greater good in this pathway. This subset of clinical investigation stands in contrast to the “second translational block,” a term coined by the Institute of Medicine's Clinical Research Roundtable to refer to the difficulties encountered in achieving widespread implementation of treatments previously determined to be safe and efficacious in randomized clinical trials into everyday medical practice.