With national focus on reading and math achievement, science and social studies have received less instructional time. Yet, accumulating evidence suggests that content knowledge is an important predictor of proficient reading. Starting with a design study, we developed content-area literacy instruction (CALI) as an individualized (or personalized) instructional program for kindergarteners through 4th graders to build science and social studies knowledge. We developed CALI to be implemented in general education classrooms, over multiple iterations (n = 230 students), using principles of design-based implementation research. The aims were to develop CALI as a usable and feasible instructional program that would, potentially, improve science and social studies knowledge, and could be implemented during the literacy block without negatively affecting students' reading gains (i.e., no opportunity cost). We then evaluated the efficacy of CALI in a randomized controlled field trial with 418 students in kindergarten through 4th grade. Results reveal that CALI demonstrates promise as a usable and feasible instructional individualized general education program, and is efficacious in improving social studies (d = 2.2) and science (d = 2.1) knowledge, with some evidence of improving oral and reading comprehension skills (d = 0.125).