School personnel make a variety of decisions within multitiered problem-solving frameworks, including the decision to assign a student to group-based support, to design an individualized support plan, or classify a student as eligible for special education. Each decision is founded upon a judgment regarding whether the student has responded to intervention. These and other conclusions are inherently causal, thus requiring that educators carefully consider the internal, construct, and conclusion validity of each decision to ensure its defensibility. Researchers have identified multiple variables that are likely to moderate these validities, including the integrity with which interventions are implemented, the psychometric adequacy of progress-monitoring tools, the extent to which interventions and supports are matched to a student’s needs, and the approach to single-case research design. We therefore review each of these variables in the interest of assisting practitioners to design acceptable and valid multi-tiered frameworks of prevention and service delivery.