The authors summarize evidence from a multiyear study with secondary students with reading difficulties on (a) the potential efficacy of primary-level (Tier 1), secondary-level (Tier 2), and tertiary-level (Tier 3) interventions in remediating reading difficulties with middle school students, (b) the likelihood of resolving reading disabilities with older students with intractable reading disabilities, (c) the reliability, validity, and use of screening and progress monitoring measures with middle school students, and (d) the implications of implementing response to intervention (RTI) practices at the middle school level. The authors provide guidance about prevailing questions about remediating reading difficulties with secondary students and discuss future directions for research using RTI frameworks for students at the secondary level.