Ubiquitination, a crucial post-translational modification, significantly influences cancer initiation and progression. This review emphasizes its roles in programmed cell death (including apoptosis, ferroptosis, and autophagy), drug resistance, and cancer therapy. In cell death pathways, ubiquitination through K48 and K63 linkages regulates proteins such as Bcl-2, ACSL4, and p62, thereby affecting cancer cell survival. The dysregulation of ubiquitin-specific proteases (USPs), such as USP1 and USP22, leads to uncontrolled cell cycle progression and abnormal DNA repair, which promotes tumorigenesis. In the context of drug resistance, ubiquitination modifies ABC transporters and DNA repair enzymes, facilitating chemotherapy resistance. Additionally, the inhibition of ferroptosis and autophagy-related ubiquitination allows cancer cells to evade apoptosis. In immunotherapy, ubiquitination plays a role in the degradation of PD-1 and PD-L1, as well as in antigen presentation, thereby shaping the immune microenvironment. Therapeutic strategies, including proteasome inhibitors, E3 ligase inhibitors, and PROTACs show promise. Targeting USPs or employing stress-responsive PROTACs may help overcome resistance, with combination therapies emerging as a key area of research. Future studies should aim to clarify the dynamics of the ubiquitination network, develop selective inhibitors, and explore precision medicine for clinical applications.