This article discusses methodological strengths and limitations of federally managed postsecondary data with American Indian/Alaska Native (AI/AN) college student populations. To support understanding, we define fundamental research and measurement validity concepts associated with credible quantitative research. The validity concepts are then applied to dominant culture and AI/AN postsecondary persistence theories. Challenges of conducting scientifically valid research with AI/AN populations using large federally available datasets are considered within the described research and measurement validity frameworks. Our critique focuses on vital needs for culturally relevant constructs and AI/AN subpopulation-specific studies. Our discussion concludes with implications and policy recommendations for postsecondary research with AIs/ANs.