Tumor cells evade the body’s immune system by expressing immune checkpoints. By blocking these immune checkpoints, immune checkpoint inhibitors can promote anti-tumor immune response and elicit strong anti-tumor effects. As an innate immune checkpoint, CD47 is widely overexpressed in different malignant tumors. It assists tumor cells to evade immune surveillance and attack by interacting with signal regulatory protein α (SIRPα) on macrophages to inhibit the phagocytosis of tumor cells by macrophages. Blocking CD47/SIRPα signaling axis can activate the phagocytosis of macrophages on tumor cells and promote the anti-tumor immune response. However, due to the complex tumor micro-environment, blocking a single signaling pathway on immune cells only has limited or mild effects. Moreover, the tumor response rate is low with drug targeting the CD47/SIRPα signaling axis alone and there are serious adverse reactions. In order to overcome these problems and improve the antitumor effect, combining drugs targeting the CD47/SIRPα signaling axis with other anti-tumor therapies becomes one of the most effective strategies. This article reviews the recent research progress on the CD47/SIRPα signaling axis and combination therapy strategies based on drugs targeting the CD47/SIRPα signaling axis.