This study identified profiles of 13 risk factors across child, family, school, and neighborhood domains in a diverse sample of children in kindergarten from four US locations (n = 750; 45% minority). It then examined the relation of those early risk profiles to externalizing problems, school failure, and low academic achievement in Grade 5. A person-centered approach, latent class analysis, revealed four unique risk profiles, which varied considerably across urban African American, urban White, and rural White children. Profiles characterized by several risks that cut across multiple domains conferred the highest risk for negative outcomes. Compared to a variable-centered approach, such as a cumulative risk index, these findings provide a more nuanced understanding of the early precursors to negative outcomes. For example, results suggested that urban children in single-parent homes that have few other risk factors (i.e., show at least average parenting warmth and consistency and report relatively low stress and high social support) are at quite low risk for externalizing problems, but at relatively high risk for poor grades and low academic achievement. These findings provide important information for refining and targeting preventive interventions to groups of children who share particular constellations of risk factors.