Abstract: A comprehensive understanding of the key molecular events underlying the origin and early evolution of malignant tumors is crucial for cancer prevention, early diagnosis, and the development of intervention strategies. Traditionally, it is considered that driver gene mutations are the decisive drivers in cancer occurrence and progression. However, recent studies have uncovered extensive somatic mutations and clonal expansions in morphologically normal tissues, which rarely progress to malignancy. This suggests that genetic mutations alone may not be sufficient for cancer development, and that other critical driver events may contribute to the irreversible transformation of parenchyma cells and their local microenvironment into invasive lesions. This review aims to provide a brief review of the intrinsic and extrinsic determinants of the origin and the early stages of tumorigenesis, in an effort to offer insights into subsequent research on the mechanisms of cancer occurrence as well as the early diagnosis and treatment of cancer.