Multi-Tiered System of Supports (MTSS) is a framework for organizing and providing a tiered instructional continuum to support learning for all students. MTSS has the potential to meet the academic and behavioral needs of all students. However students with the most significant cognitive disabilities often are not included in this framework even though they should be. The purpose of this Brief is to provide suggestions for ways in which MTSS can include students with the most significant cognitive disabilities so that MTSS provides a whole school and whole district approach to be implemented by educators. Ideas for how to make MTSS fully inclusive of all students are presented following a short history of MTSS and a summary of current MTSS models. [This report was published jointly with the TIES Center.]