Hypospadias is the second most common genital anomaly in children. The etiology of hypospadias remains unknown in the overwhelming majority of patients. Herein, I review the etiology of hypospadias and propose that hypospadias can be explained by a two-hit hypothesis: genetic susceptibility plus environmental exposure to endocrine disruptors. The strategy to prevent hypospadias should be focused on (1) identifying genetic susceptibility prior to pregnancy and (2) identifying and eliminating exposure to potential toxic endocrine disruptors that effect urethral development.