Multiple competing theories have sought to explain the complex phenomenon of oncogenesis, each emphasizing different causal layers—genetic, cellular, epigenetic, metabolic, and tissular. The dominant somatic mutation theory (SMT) posits that cancer arises from sequential genetic mutations in oncogenes and tumor suppressor genes, forming the foundation of targeted and precision oncology. Variants like the “bad luck” hypothesis and the cancer stem cell (CSC) theory frame cancer as a consequence of stochastic mutations or plastic transitions into stem-like states. Epigenetic theories emphasize gene regulation through methylation, histone modification, and noncoding RNAs, while metabolic models trace cancer’s origins to Warburg’s hypothesis of mitochondrial dysfunction. Tissue-level models, including the tissue organization field theory (TOFT), highlight microenvironmental dysfunction and stroma-epithelial interactions. Recent integrative frameworks, such as ground state theory, seek to reconcile these views by acknowledging both intrinsic and extrinsic determinants of transformation. Clinical advances, particularly immunotherapies, underscore the significance of tissue-level targeting. These five theoretical domains are not mutually exclusive; instead, they reflect a layered reality in which genetic and nongenetic, cellular and supra-cellular processes intersect to drive malignancy. A systems-level, pluralistic approach may ultimately prove most effective for developing both explanatory models and therapeutic interventions across cancer types.