The dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade (ICB), which could potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified; some of them have exhibited potential druggability and have been approved by the Food and Drug Administration (FDA) for clinical treatments. However, the limited responses and immune-related adverse events (irAEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.