Purpose: This article provided a comprehensive overview of select challenges that oftentimes prevent minority-serving institutions (MSIs) in the United States (i.e., historically Black colleges/universities, Hispanic-serving institutions, and American Indian tribal colleges/universities) from participating optimally in the federal research enterprise (i.e., National Institute on Disability, Independent Living, and Rehabilitation Research and National Institutes of Health). Methods: The authors completed a detailed synthesis of the available peer review and grey literature and policy on the subject matter while using the structural empowerment and critical mass models as theoretical lenses. Results: Select research infrastructure issues (i.e., restrictive administrative culture, heavy teaching and service practices, inefficient offices of sponsored programs, the lack of research seed money units, inefficient institutional review boards, and limited library resources and technology infrastructure) and limited training opportunities (i.e., postdoctoral fellowship training programs, and grant writing training) are important considerations in MSI research capacity and productivity context. Conclusions: New state-of-the-science research capacity building approaches, paradigms, and conceptual models that address individual MSI-based investigators' research skill development needs, institutional research infrastructure systems weaknesses, and federal research agency systems and policy issues need to be explored and scaled up for further efficacy testing through rigorous scientific methods.