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The regional enrollment of participants in pivotal randomized controlled trials (RCTs) often does not represent the regional distribution of cardiovascular diseases. Over the past four decades, trials have enrolled participants primarily from North America and Europe, limiting the global generalizability of findings. In this Perspective, we review the evolution of regional participation in RCTs, using heart failure as a case study to assess temporal trends, current gaps in representativeness and opportunities for improvement. We assess the regulatory, logistical and financial barriers to clinical trial enrollment in underrepresented regions. We examine the manner in which global regions have been classified in trials, and propose a standardized regional classification system for reporting and subgroup analysis. To improve regional representativeness, we suggest targeted strategies that address barriers faced at the national, regulatory, sponsor or funder, institution and patient level. We also recommend the use of a representativeness index during trial planning and site selection to enhance regional representativeness. Expanding trial participation beyond historically dominant regions could be a key step in improving trial efficiency, external validity and global health equity.