Interest in multi-tiered systems of support (MTSS) as a process for school system reform is gaining momentum nationwide. Confusion exists as to what MTSS is and how response to intervention (RtI) and professional learning communities (PLCs) are related to its implementation. This article seeks to reconcile these differences through a descriptive case study that examines superintendent perceptions regarding opportunities and obstacles inherent to MTSS implementation. Sixty-six percent of one state's 41 superintendents completed a MTSS readiness survey and nine were purposively chosen to be interviewed based on their responses. The article discussion includes a description of MTSS concepts related to implementation, and the findings can help to inform districts that are looking to refine systems improvement efforts. (Contains 2 tables and 1 figure.)