Recent advances in non-genetic and evolutionary cancer genomics increasingly challenge the long-standing mutational and molecular interpretations of cancer. At the core of this shift lies a fundamental contradiction between the traditional multicellular interpretation of cancer and the emerging concept of a self-organizing unicellular system. Traditional models view cancer as an aberration within the multicellular framework. In contrast, evolutionary research reveals that cancer reflects an inversion to unicellularity, predominantly expressed in the stemgermline and its archaic unicellular genome. The origins of cancer’s stemgermline trace back to an ancestral lineage (Urgermline) whose genomic and regulatory features have been inherited by all modern stem cell lineages. Since the lifestyle of this Urgermline evolved during periods of historical hypoxia (approximately 1,600–800 million years ago [Mya]) and gradual atmospheric oxygen increase (800–550 Mya), parasitic unicellular systems, such as amoebae and cancer—particularly their stemgermlines—benefit considerably from the low oxygen gradients present in tissues and organs that offer specific key inducers, suppressors, regulators, and effectors of cancer cell systems. One could argue that cancer reconstructs an autonomous cell system, mirroring developments from the Meso- and Neoproterozoic, and the evolutionary transition toward early multicellularity. As a result, cancer follows fundamentally different rules than those governing stable multicellular systems. Accordingly, conventional multicellular concepts such as uncontrolled proliferation, genomic chaos, genomic instability, and loss of genomic integrity are inadequate when viewed through evolutionary biology. The present work compares the mutational-molecular perspective of cancer with a non-genetic, evolutionary framework.