Transglutaminase 2 (TG2) is a multifunctional enzyme with widespread expression and involvement in various cellular processes. It plays a crucial role in cancer development and progression by modulating the tumor microenvironment and influencing multiple signaling pathways. TG2 can act both as an anti- and pro-apoptotic factor, depending on the cellular context and its structural conformation. Its expression is altered in various cancers, including melanoma, breast cancer, ovarian cancer, colorectal cancer, leukemia, pancreatic cancer, and lung cancer. TG2 is involved in cell proliferation, invasion, drug resistance, and metastasis formation. It interacts with key proteins and signaling pathways, such as TGF-β, β-catenin, ERK1/2, p53, and Rb, to promote cancer hallmarks. TG2 also modulates the extracellular matrix (ECM) and angiogenesis, affecting tumor growth and immune response. The role of TG2 in cancer is highly context-specific, and its regulation by various factors like Ca²⁺ and GTP influences its activity. Targeting TG2's multiple activities could be a promising therapeutic strategy for several cancers.Transglutaminase 2 (TG2) is a multifunctional enzyme with widespread expression and involvement in various cellular processes. It plays a crucial role in cancer development and progression by modulating the tumor microenvironment and influencing multiple signaling pathways. TG2 can act both as an anti- and pro-apoptotic factor, depending on the cellular context and its structural conformation. Its expression is altered in various cancers, including melanoma, breast cancer, ovarian cancer, colorectal cancer, leukemia, pancreatic cancer, and lung cancer. TG2 is involved in cell proliferation, invasion, drug resistance, and metastasis formation. It interacts with key proteins and signaling pathways, such as TGF-β, β-catenin, ERK1/2, p53, and Rb, to promote cancer hallmarks. TG2 also modulates the extracellular matrix (ECM) and angiogenesis, affecting tumor growth and immune response. The role of TG2 in cancer is highly context-specific, and its regulation by various factors like Ca²⁺ and GTP influences its activity. Targeting TG2's multiple activities could be a promising therapeutic strategy for several cancers.