As most patients with sickle cell disease (SCD) do not have access to curative therapies, the availability of drug therapies that can modify disease severity remains highly desirable. Despite an increased understanding of the pathophysiology of SCD, only four drugs are approved by the US Food and Drug Administration. Most drug trials in SCD have involved the use of acute pain episodes as the primary clinical endpoint. These studies have typically been to prevent or to shorten the duration of such episodes. To date, no drugs have received regulatory approval for shortening the duration of acute vaso-occlusive complications, likely highlighting the complex pathophysiology of acute pain episodes. Trials to prevent acute pain episodes have largely evaluated those episodes requiring healthcare utilization as a surrogate endpoint. However, with differences in culture and healthcare practices amongst countries, healthcare utilization may not reliably predict clinically important effects on acute pain episodes. This Perspective discusses issues related to the use of healthcare utilization as the primary endpoint for prevention trials of acute pain episodes and highlights the importance of evaluating patient-reported outcomes as well as other SCD-related complications as outcome measures.