With increasingly diverse students, schools and districts are under pressure to meet rigorous standards and raise student achievement in reading and literacy. Most teachers respond by differentiating their instruction to some extent, but not all scholars and educators agree on whether differentiated instruction works. This systematic review and meta-analysis seeks to determine the effects of Tier 1 differentiation, which is provided by the general education classroom teacher, on literacy outcomes. Distinguishing between designed differentiation and interactional differentiation, the authors provide multiple examples of content, process, and product differentiation in the context of literacy instruction. Reviewing more than 20 years of literacy research, the authors located 18 studies with 25 study cohorts. Outcomes include fluency, decoding, letter-word reading, vocabulary, comprehension, and writing achievement. The overall weighted mean effect size (g) was +0.13 (p = .002) with 88% of the individual point estimates being positive. Overall, the findings indicate that differentiated literacy instruction is an effective evidence-based practice at the elementary level. When teachers are supported to differentiate instruction, students have significantly higher literacy achievement scores, particularly for letter-word (g = +0.20, p = .014) and writing outcomes (g = +0.96, p < .001). The most successful programs took very different approaches to differentiation, including individualization, choice, and an alternate curriculum. However, across the studies, there was an alarming lack of information about the decision-making processes used to guide differentiation and there were no experimental or quasi-experimental studies on guided reading. This review may be helpful as schools clarify their vision for literacy differentiation.