Many studies have demonstrated the efficacy of reading comprehension interventions for struggling readers, including students with learning disabilities. Yet, some readers continue to struggle with comprehension despite receiving these interventions. In this article, we argue that an explicit link between cognitive psychology and intervention research contributes to knowledge regarding for whom and under what conditions reading comprehension interventions are most likely to be beneficial. First, we provide a brief overview of a cognitive perspective on reading comprehension. Next, we illustrate an application of this perspective by describing a collaborative project in which we examined interactions among reader characteristics, text properties, and instructional contexts. Last, we highlight directions for future research and implications for practice.