This publication provides research-based guidance for intensifying instruction in reading and mathematics for students with significant learning difficulties, including students with disabilities, in kindergarten through grade 12. The guide gives technical assistance providers and states information reflecting "best practices" for implementing intensive interventions to improve education practices for struggling students, including those who receive special education. It can also be used as a resource for instructional specialists and special education teachers who are searching for broad guidelines on the design and delivery of intensive interventions. With those goals in mind, the authors present a brief review of the research on intensifying instruction for struggling students. Specifically, they discuss: (1) integrating strategies that support cognitive processes (e.g., self-regulation and memory) with academic instruction and aligning this instruction with learner needs; (2) differentiating instructional delivery by making it more explicit and systematic and by increasing opportunities for feedback; (3) increasing instructional time; and (4) reducing group size. The guide includes the following resources: (1) practice guidelines (in the form of questions and answers) that can inform the design and delivery of intensive interventions; (2) example lessons (see the Appendix) that illustrate the intensification of key areas of instructional delivery (i.e., making lessons more explicit and systematic and increasing the opportunities for student response and feedback); and (3) a list of resources for further reading and extended learning. Although this guide is not a comprehensive review of the literature, it does offer guidelines for instructional decision-makers on adapting and modifying instructional practices to deliver appropriate, responsive instruction for students with learning difficulties. Example Lessons are appended. (Contains 1 table and 1 footnote.)