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After a decade of intensive research on two-dimensional (2D) materials inspired by the discovery of graphene, the field of 2D electronics has reached a stage with booming materials and device architectures. However, the efficient integration of 2D functional layers with three-dimensional (3D) systems remains a significant challenge, limiting device performance and circuit design. In this review, we investigate the experimental efforts in interfacing 2D layers with 3D materials and analyze the properties of the heterojunctions formed between them. The contact resistivity of metal on graphene and related 2D materials deserves special attention, while the Schottky junctions formed between metal/2D semiconductor or graphene/3D semiconductor call for careful reconsideration of the physical models describing the junction behavior. The combination of 2D and 3D semiconductors presents a form of p-n junctions that have just marked their debut. For each type of the heterojunctions, the potential applications are reviewed briefly.