<p>Intrinsic and extrinsic factors influence cancer cell identity throughout its lifespan. During tumor progression and metastasis formation, cancer cells are exposed to different environmental stimuli, resulting in a stepwise cellular reprogramming. Similar stepwise changes of cell identity have been shown as a major consequence of cancer treatment, as cells are exposed to extracellular stress that can result in the establishment of subpopulations exhibiting different epigenetic and transcriptional patterns, indicating a rapid adaptation mechanism of cellular identity by extrinsic stress factors. Both mechanisms, tumor progression-mediated changes and therapy response, rely on signaling pathways affecting the epigenetic and subsequent transcriptional landscape, which equip the cells with mechanisms for survival and tumor progression. These non-genetic alterations are propagated to the daughter cells, indicating a need for successful information propagation and transfer to the daughter generations, thereby allowing for a stepwise adaptation to environmental cues. However, the exact mechanisms how these cell identity changes are occurring, which context-specific mechanisms are behind and how this can be exploited for future therapeutic interventions is not yet fully understood and exploited. In this review, we discuss the current knowledge on cell identity maintenance mechanisms intra- and intergenerational in development and disease and how these mechanisms are altered in cancer. We will as well address how cancer treatment might target these properties.</p>