Youth runaway behavior and homelessness (RHY) in the U.S. is increasingly common, with prevalence estimated at 1–1.7 million youth. RHY have multiple, overlapping problems often including poor physical and mental health, frequent street victimization, and histories of physical and sexual abuse. Further, current street victimization interacts with childhood abuse to produce complex, unique presentations of traumatic symptoms and related disorders in runaway and homeless youth. This review paper explores (1) the role of childhood trauma in the genesis of runaway and homeless behavior, and (2) how childhood trauma interacts with street victimization to create vulnerability to psychopathology. In response to the trauma needs of RHY, we conducted a systematic review of the state of the current literature on trauma-informed interventions for RHY. We conclude that the field currently lacks empirically validated trauma interventions in RHY. However, theoretically plausible frameworks do exist and could be the basis for future research and intervention development.