The article examines the scientific and didactic foundations of constructing the content of natural science subjects in specialized classes of general education schools. Based on the principles of the educational standard, interdisciplinary connections, continuity, and progression, the approaches to selecting educational material are analyzed. The features of radial, stepwise, and concentric approaches to structuring the content of natural sciences are compared, with their advantages and disadvantages identified. The authors demonstrate the effectiveness of the principles of generalization and cyclicity in organizing educational content around theories. It is also shown that these principles are implemented through clustering subject matter around fundamental theories. The article highlights the importance of the principles of fundamentality, scientific validity, applicability, professional orientation, humanization, and information-technological orientation in selecting educational content under the conditions of specialized differentiated instruction. The research results include recommendations aimed at developing students’ scientific worldview, theoretical thinking, and research skills in the teaching of natural sciences in specialized classes.