Two-dimensional materials and single-atom catalysts are two frontier research fields in catalysis. A new category of catalysts with the integration of both aspects has been rapidly developed in recent years, and significant advantages were established to make it an independent research field. In this Review, we will focus on the concept of two-dimensional materials confining single atoms for catalysis. The new electronic states via the integration lead to their mutual benefits in activity, that is, two-dimensional materials with unique geometric and electronic structures can modulate the catalytic performance of the confined single atoms, and in other cases the confined single atoms can in turn affect the intrinsic activity of two-dimensional materials. Three typical two-dimensional materials are mainly involved here, i.e., graphene, g-C3N4, and MoS2, and the confined single atoms include both metal and nonmetal atoms. First, we systematically introduce and discuss the classic synthesis methods, advanced characterization techniques, and various catalytic applications toward two-dimensional materials confining single-atom catalysts. Finally, the opportunities and challenges in this emerging field are featured on the basis of its current development.