Suicide is the second leading cause of death among youth aged 10-25 years, and approximately one in six adolescents reported serious suicidal ideation in the past year (Centers for Disease Control and Prevention [CDC] in Web-based Injury Statistics Query and Reporting System (WISQARS). http://webappa.cdc.gov/cgi-bin/broker.exe, 2017). Schools are a unique environment in which to identify and respond to youth suicide risk, yet the research base for school-based suicide prevention programs is limited due to challenges with implementation and evaluation. The purpose of this article is to review best practice approaches and existing empirical support for school-based suicide prevention and to present a framework for how these efforts can be embedded within multi-tiered systems of support (MTSS). In line with the Substance Abuse and Mental Health Services Administration [SAMHSA] (Preventing suicide: a toolkit for high schools. https://store.samhsa.gov/shin/content//SMA12-4669/SMA12-4669.pdf, 2012) framework for suicide prevention in schools, the article overviews existing programs for student education, staff training, and screening, noting where these programs may be situated across tiers of intervention. This is followed by a review of school-related outcomes of existing suicide prevention programs, which highlights the limitations of existing research. Because there are only two school-based prevention programs with evidence for reducing suicide risk in students, the authors encourage school staff to implement best practice recommendations in collaboration with school mental health professionals who can provide ongoing evaluation of program effectiveness, as well as with researchers who are able to design and conduct outcome studies addressing the limitations of current research. Findings also underscore the need for greater integration of suicide prevention programming with existing school initiatives such as MTSS, which aligns with a growing focus in the field of suicide prevention on "upstream approaches."