Epithelial cancers are thought to evolve through a competitive process of mutation and selection in which the serial acquisition of oncogenic mutations confers an increasing fitness advantage, culminating in neoplastic transformation, tumour invasion, and metastasis. This programme often initiates through a phase of field cancerization in which mutant clones expand within the context of physiologically normal-looking tissue. To mitigate the risks associated with field cancerization, protection strategies have evolved that resist mutant clone expansion, from the development of anatomical features that limit clone growth to the activation of genetic and immunological surveillance mechanisms. Yet, despite these insights, our knowledge of how oncogenes act alone or in combination to evade these protection mechanisms to drive clonal pathogenesis remains largely unknown. Here, by combining a unique genetic lineage tracing strategy with comparative single-cell genomics and quantitative modelling-based methods, we will define the mechanisms that mediate mutant clone competition. By placing an emphasis on the squamous and columnar epithelia of the GI tract, we will investigate whether and how injury and inflammatory cues, as well as ageing, enable tumorigenic clones to evade natural protection strategies, functioning as a “second hit” in driving field cancerization and neoplastic transformation. Finally, to explore the translational relevance of our findings, we will combine DNA sequencing, single-cell methods, and spatial transcriptomics with the design and genetic manipulation of state-of-the-art 3D organ cultures to investigate mutant clone dynamics in human tissue. By tracing the origins of clonal pathogenesis, these findings promise insights into the design of new prevention, detection, and treatment strategies, targeting the early stages of cancer progression.