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Homeless mothers experience disproportionately high rates of major depressive disorder compared with the general population. Stressed by their circumstances, these women struggle to protect their families. Children living with a depressed parent have poorer medical, mental health, and educational outcomes. Despite the adverse impact on children, depression among mothers experiencing homelessness remains unacknowledged, unrecognized, and untreated. This article reviews the evidence supporting preventive and therapeutic interventions with low-income and homeless mothers and children, and finds that few services have been adapted and evaluated for use in the homelessness service system. Based on the robust evidence describing positive outcomes in programs for low-income parents with depression, the authors propose guidelines for adapting and implementing services directly by programs serving homeless families. Once families are housed and urgent issues addressed, they recommend assessing all family members, routinely providing culturally competent parenting supports, trauma-informed services, and treatment for major depressive disorders. They also emphasize the critical importance of creating child-centered spaces and developmental services for the children. To ensure quality care, training must be available for the staff. Given the increasing numbers of homeless families and high rates of maternal depression and its negative impact on children, support for these programs should become a high public health priority.