The appropriate selection of response variables for clinical trials of new therapies for acute heart failure (AHF) is a complex process with major trade-offs. For one therapeutic approach to be considered superior to another, it must produce clinically significant improvements in making patients live longer, making patients feel better, or saving resources without adversely affecting these two goals. This review outlines factors that complicate AHF end-point selection, discusses a variety of end points used in recently completed and ongoing AHF studies, and suggests directions for future design and standardization of end points across AHF trials.