Homelessness among children has been called a national tragedy. Homeless children, by virtue of their unique situation, are particularly vulnerable for early initiation of and sustained participation in substance abuse behaviors. The authors describe homeless children in relation to drug abuse etiology research, discuss current prevention strategies, suggest necessary components of an interdisciplinary prevention curriculum for homeless preschool children, and delineate methods for delivering the curriculum to the children. Nurses, given their unique role in the healthcare delivery system as well as a holistic world view, are in an unparalleled position to facilitate the design and implementation of such curricula.