Benincasa hispida, from tropical Asia, is cultivated primarily for its edible fruit. To explore its domestication and ethnobotany, we made collections from two regions where it may have been domesticated: (1) Southern China/Southeast Asia, represented by southern Yunnan Province (China) and northern Laos; and (2) the Indian subcontinent, represented by southeastern Nepal. Domestication has resulted in diverse fruit sizes, shapes, and colors; seed sizes and shapes; and, in some accessions, the loss of tendrils. Modern cultivars have larger fruit, earlier flowers, and lower nutritional content than traditional cultivars. Allozyme diversity was low, divergence between these two regions was low, and these results do not clarify the place of domestication. The greater morphological diversity of plants from Yunnan and Laos, as compared to Nepal, suggests domestication in the former region. In all accessions, male flowers precede females. Benincasa hispida is prominent in some traditional stories and rituals.