Combination therapy, which involves the use of two or more therapeutic agents, is a cornerstone of cancer treatment. This approach enhances efficacy by targeting key pathways synergistically or additively, potentially reducing drug resistance and providing therapeutic benefits such as reducing tumor growth, metastasis, and cancer stem cell populations. The 5-year survival rates for most metastatic cancers remain low, and the development of new anti-cancer drugs is costly and time-consuming. Therefore, new strategies that target survival pathways efficiently and effectively are being explored. One such approach is repurposing therapeutic agents initially used for other diseases, which can reduce costs and increase cost efficiency. This review discusses important pathways commonly targeted in cancer therapy, including the Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), and carbonic anhydrase inhibitor (CAI) pathways. It also reviews repurposed or primary anti-cancer agents that have gained popularity in clinical trials since 2012. The review highlights the potential of combination therapies, such as those involving curcumin, resveratrol, squalene, sulforaphane (SFN), and acetazolamide (AZ), in enhancing therapeutic outcomes. Additionally, it explores the role of epigenetic modifiers like HDACi and the importance of targeting autocrine growth factors and angiogenesis pathways in cancer treatment.Combination therapy, which involves the use of two or more therapeutic agents, is a cornerstone of cancer treatment. This approach enhances efficacy by targeting key pathways synergistically or additively, potentially reducing drug resistance and providing therapeutic benefits such as reducing tumor growth, metastasis, and cancer stem cell populations. The 5-year survival rates for most metastatic cancers remain low, and the development of new anti-cancer drugs is costly and time-consuming. Therefore, new strategies that target survival pathways efficiently and effectively are being explored. One such approach is repurposing therapeutic agents initially used for other diseases, which can reduce costs and increase cost efficiency. This review discusses important pathways commonly targeted in cancer therapy, including the Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), and carbonic anhydrase inhibitor (CAI) pathways. It also reviews repurposed or primary anti-cancer agents that have gained popularity in clinical trials since 2012. The review highlights the potential of combination therapies, such as those involving curcumin, resveratrol, squalene, sulforaphane (SFN), and acetazolamide (AZ), in enhancing therapeutic outcomes. Additionally, it explores the role of epigenetic modifiers like HDACi and the importance of targeting autocrine growth factors and angiogenesis pathways in cancer treatment.