The 21st-century translational science campaign could lead to an increase in first-in-human (FIH) trials. As tests of investigational interventions move from the laboratory to human research, scientists, officials, and review committees should address ongoing concerns about the ethics of FIH trials. In this article, I describe three ethical considerations relevant to all FIH trials: (1) the requirement for adequate preclinical research; (2) study design safeguards; and (3) choice of subject population. I also examine specific ethical considerations relevant to the three subject populations (healthy volunteers, seriously ill patients lacking standard treatment options, and stable patients) involved in FIH research. I recommend a variety of actions that could increase subject protection and the value of the information generated in FIH trials.