Patients presenting with acute heart failure (AHF) represent a heterogeneous population with respect to demographics, clinical profiles, and precipitating factors. Despite this, most clinical trials have treated the study population as a homogeneous group in an attempt to achieve adequate statistical power for endpoint analysis. This approach has proven to be of little value in the development of new agents for treatment of AHF. By contrast, the phase III clinical trial of relaxin focused on a subset of AHF patients who were normotensive or hypertensive and who had moderate renal impairment. The study patients, who were primarily from Eastern Europe, represented a population that would be expected to have less genetic variability than the study populations in larger multinational AHF trials. A focused study design targeting specific patient profiles should be considered for future clinical AHF trials that investigate new therapies or compare the effectiveness of existing therapies.