Social-cognitive and emotional factors as well as behavior problems contribute to the social difficulties experienced by many students with or at high risk for emotional and behavioral disorders (EBDs). The way that teachers and peers treat and respond to these students can either mitigate or exacerbate their challenges in establishing and maintaining positive social relationships and adjusting adaptively to the school context. Managing behavior alone does not address the self-regulatory skills deficits that contribute to social maladjustment, nor does it create socializing contexts that can support self-regulatory skill development. This article reviews research on neurodevelopmental processes and contextual constraints that contribute to the social-emotional difficulties of students with or at high risk for EBD. Implications for intervention design are explored, with a focus on the need for more consistent use of tiered social-emotional learning programs in schools to promote the self-regulation skills and social competence of vulnerable students with or at risk of EBDs. The authors also highlight the need for future research to enhance capacity to support tiered systems of intervention in schools and tailor them effectively to meet the varied needs of these students. [For the corresponding grantee submission, see ED610547.]