MissionSAFE began when Sister Anne Carrabino, S.S.S. and Nikki Flionis met in a Master's program at Harvard's Kennedy School. Beginning in 1998, Anne and Nikki with a small multi-cultural staff outreached to and worked with families and children at the soon to be re-built Mission Main housing development. The development had had a reputation for gunfire, arson and major drug dealing, and families still feared retribution for organizing or seeking out positive activities.

After working for two years with families, through the demolition and rebuilding of the development, MissionSAFE became a 501 c 3 non-profit in 2000 with a focus on adolescent youth and young adults, addressing trauma through a relational approach, building resilience, social and life skills, and beginning the focus on job-readiness internships, community service, leadership development and civic engagement as well as strategies for academic success. MissionSAFE opened its doors to youth from Mission Hill, lower Roxbury, Roxbury, Dorchester, Mattapan and other Boston neighborhoods. In 2005, MissionSAFE expanded to two sites: adding a Charlestown program while maintaining its Roxbury program in Mission Hill.

MissionSAFE began as a vision of Sister Anne Carrabino, a nun whose past work had taken her to South Central Los Angeles and El Salvador; and Nikki Flionis, a community activist from Boston. The two met while part of the mid-career program at the Harvard Kennedy School. They shared a passion for social justice and a belief that all youth should have the support and resources to discover and utilize their unique gifts and full potential. They also realized that for at-risk youth to overcome obstacles and achieve their potential, they needed safe and ongoing relationships with healthy adults in a safe, consistent space. Without the safe, relational component, developing enough trust to explore potential and build their skills was not possible.