This review article explores the molecular mechanisms and interventional targets in tumor initiation and early tumorigenesis. It highlights that while oncogenic mutations in normal cells are the initial event, their transformation into cancer is a rare process, indicating the involvement of additional driver events. The article emphasizes the role of environmental risk factors and epigenetic alterations in influencing early clonal expansion and malignant evolution. Clonal evolution in tumorigenesis is a complex interplay between intrinsic cell identities and extrinsic selective pressures. The review discusses genetic, epigenetic, and external driver events and their effects on the co-evolution of transformed cells and their ecosystem during tumor initiation and early malignant evolution. It also explores how these molecular processes can be used to predict high-risk individuals and develop strategies to intercept malignant transformation. The article reviews the historical research on tumor initiation, the molecular drivers of tumorigenesis, including genetic alterations, epigenetic changes, and environmental factors, and their interactions in promoting tumor development. It provides insights into the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation.This review article explores the molecular mechanisms and interventional targets in tumor initiation and early tumorigenesis. It highlights that while oncogenic mutations in normal cells are the initial event, their transformation into cancer is a rare process, indicating the involvement of additional driver events. The article emphasizes the role of environmental risk factors and epigenetic alterations in influencing early clonal expansion and malignant evolution. Clonal evolution in tumorigenesis is a complex interplay between intrinsic cell identities and extrinsic selective pressures. The review discusses genetic, epigenetic, and external driver events and their effects on the co-evolution of transformed cells and their ecosystem during tumor initiation and early malignant evolution. It also explores how these molecular processes can be used to predict high-risk individuals and develop strategies to intercept malignant transformation. The article reviews the historical research on tumor initiation, the molecular drivers of tumorigenesis, including genetic alterations, epigenetic changes, and environmental factors, and their interactions in promoting tumor development. It provides insights into the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation.