Prior research reveals high unemployment rates among homeless youth. The literature offers many examples of using evidence-informed and evidence-based supported employment models with vulnerable populations to assist them in obtaining and maintaining employment and concurrently addressing mental health challenges. However, there are few examples to date of these models with homeless youth with mental illness. The purpose of this article was thus to describe a methodology for establishing a university-agency research partnership to design, implement, evaluate, and replicate evidence-informed and evidence-based interventions with homeless youth with mental illness to enhance their employment, mental health, and functional outcomes. Data from two studies are used to illustrate the relationship between vocational skill-building/employment and mental health among homeless youth. The article concludes with a discussion of the implications of conducting community-based participatory employment and clinical intervention research. The author highlights the opportunities and tensions associated with this approach.