Differentiated instruction is a pedagogical-didactical approach that provides teachers with a starting point for meeting students' diverse learning needs. Although differentiated instruction has gained a lot of attention in practice and research, not much is known about the status of the empirical evidence and its benefits for enhancing student achievement in secondary education. The current review sets out to provide an overview of the theoretical conceptualizations of differentiated instruction as well as prior findings on its effectiveness. Then, by means of a systematic review of the literature from 2006 to 2016, empirical evidence on the effects of within-class differentiated instruction for secondary school students' academic achievement is evaluated and summarized. After a rigorous search and selection process, only 14 papers about 12 unique empirical studies on the topic were selected for review. A narrative description of the selected papers shows that differentiated instruction has been operationalized in many different ways. The selection includes studies on generic teacher trainings for differentiated instruction, ability grouping and tiering, individualization, mastery learning, heterogeneous grouping, and remediation in flipped classroom lessons. The majority of the studies show small to moderate positive effects of differentiated instruction on student achievement. Summarized effect sizes across studies range from = +0.741 to +0.509 (omitting an outlier). These empirical findings give some indication of the possible benefits of differentiated instruction. However, they also point out that there are still severe knowledge gaps. More research is needed before drawing convincing conclusions regarding the effectiveness and value of different approaches to differentiated instruction for secondary school classes.