We describe findings from a series of longitudinal studies utilizing a response to intervention framework implemented over 3 years with students in Grades 6 through 8 with reading disabilities and poor reading comprehension. Students were identified based on reading comprehension scores in Grade 5 (n = 1,083) and then randomized to treatment or comparison conditions. Beginning in sixth grade, students assigned to intervention were provided treatment for 1, 2, or 3 years based on their response to instruction in each preceding year. Screening procedures, progress monitoring tools, tiers of instruction, and findings from each year of the study are reported. Additional studies investigating reading and behavioral outcomes through multi-level, growth modeling, and studies of the cognitive and neural correlates of inadequate response are also reported.