Major depression (MD) is a leading cause of disability worldwide; it arises from the action and interaction between genetic and environmental factors, and is often comorbid with other psychiatric and medical conditions. To date, upwards of 100 genetic loci have been associated with MD, giving clues to biological underpinnings. Although recent progress has yielded modest insight into the genetic architecture of MD, most studies have been in populations with European ancestry, seriously limiting precision medicine efforts. Broadening diversity of study populations will empower genomic research by expanding discovery and enhancing our understanding of the role of genomic variation in disease etiology. To fully realize the potential of pharmacogenetics and precision medicine, we will need to address the major gaps in our knowledge of the genetic and environmental risk architecture of MD across ancestries, including sex differences, to improve etiologic understanding, diagnosis, prevention, and treatment for all.