Over 34 years since its conception, research in educational settings has found evidence for the effectiveness of the 5E Instructional Model. Indeed, several studies have reported evidence of a better conceptual understanding of scientific ideas and models, positive effects on general achievement in science, and positive attitudes toward science. In this commentary, we would like to put forward the principles from cognitive sciences on how people learn which may underlie the 5E Model and that could theoretically contribute to the model's effectiveness as a learning sequence. Connections to conceptual change theory are especially highlighted.