Many children struggle to learn to read, and these difficulties can persist well into adulthood. To address this problem, researchers have investigated the processes that underlie reading. An informative body of work has thus identified basic skills (e.g., decoding, vocabulary knowledge) as necessary for successful reading. Researchers also have begun to examine comprehension skills and their contributions to the reading process. In this article we describe research from the cognitive sciences on the processes that underlie higher-order, coherence-oriented comprehension to provide an empirically and theoretically driven perspective for investigating struggling readers' difficulties. We show that this perspective is particularly beneficial in the development and assessment of instructional approaches by relating it to existing, effective interventions. Finally, we demonstrate how our own research activities have derived from this perspective and how preliminary findings extend our understanding of readers' difficulties. This work seeks to address existing challenges in the field of reading comprehension while also suggesting new ways of investigating the plight of struggling readers.