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This qualitative study investigated to what extent activity setting mediation and teacher candidate tool appropriation afford or constrain inclusive practices for students with significant support needs. Three special education teacher candidates were interviewed based on lessons they taught in inclusive general education settings. A cultural historical activity theory (CHAT) lens was applied to the filmed interview sessions. Film analysis identified four key themes: (a) activity setting, (b) relational agency, (c) context, and (d) reflective skill practice. These key components form the basis of an inclusive setting site placement theoretical framework for pre- and in-service teacher candidates implementing effective practices for students with significant support needs.