Tumorigenesis is a multistep process where oncogenic mutations in a normal cell confer clonal advantage as the initial event. Despite pervasive somatic mutations and clonal expansion in normal tissues, cancer remains rare, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recent research emphasizes the mechanisms of environmental tumor risk factors and epigenetic alterations that influence early clonal expansion and malignant evolution, independent of inducing mutations. Clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. This review summarizes the 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. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation. The earliest explanation for the origin of cancer dates back to the early 1900s, where cell-free extracts of a diseased animal were able to transmit tumors to healthy animals, suggesting that tumors originate from a unit smaller than a cell. In 1914, Theodor Boveri proposed the somatic mutation theory after observing chromosomal abnormalities in tumor cells. Subsequent studies validated DNA as the genetic material and revealed that tumorigenesis requires the accumulation of approximately six or seven mutations. The term "oncogene" was introduced in the 1960s when genetic material of certain viruses was verified to contribute to malignant transformation. The first specific tumor gene was identified in 1976 by Michael Bishop and Harold Varmus, which part of the DNA of avian sarcoma virus hybridized in the genomes of birds transforming normal cells to tumor cells, and named it as SRC. This indicated that the genetic material in our genome is capable of transforming normal cells. Subsequently, the first proto-oncogene, RAS, and tumor suppressor gene, RB1, were cloned in the early 1980s. Following this, a significant number of these two classes of cancer genes were identified, accompanied by discovery of other forms of variations, including copy number alterations, translocations and promoter hypermethylation. In the middle of 2000s, benefiting from next-generation sequencing, cancer genomics flourished and promoted the launch of large-scale tumor sequencing initiatives, such as The Cancer Genome Atlas (TCGA) in 2006 and the International Cancer Genome Consortium (ICGC) in 2007. The TCGA consortium published its Pan-Cancer Analysis of Whole Genomes (PCAWG) data inTumorigenesis is a multistep process where oncogenic mutations in a normal cell confer clonal advantage as the initial event. Despite pervasive somatic mutations and clonal expansion in normal tissues, cancer remains rare, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recent research emphasizes the mechanisms of environmental tumor risk factors and epigenetic alterations that influence early clonal expansion and malignant evolution, independent of inducing mutations. Clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. This review summarizes the 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. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation. The earliest explanation for the origin of cancer dates back to the early 1900s, where cell-free extracts of a diseased animal were able to transmit tumors to healthy animals, suggesting that tumors originate from a unit smaller than a cell. In 1914, Theodor Boveri proposed the somatic mutation theory after observing chromosomal abnormalities in tumor cells. Subsequent studies validated DNA as the genetic material and revealed that tumorigenesis requires the accumulation of approximately six or seven mutations. The term "oncogene" was introduced in the 1960s when genetic material of certain viruses was verified to contribute to malignant transformation. The first specific tumor gene was identified in 1976 by Michael Bishop and Harold Varmus, which part of the DNA of avian sarcoma virus hybridized in the genomes of birds transforming normal cells to tumor cells, and named it as SRC. This indicated that the genetic material in our genome is capable of transforming normal cells. Subsequently, the first proto-oncogene, RAS, and tumor suppressor gene, RB1, were cloned in the early 1980s. Following this, a significant number of these two classes of cancer genes were identified, accompanied by discovery of other forms of variations, including copy number alterations, translocations and promoter hypermethylation. In the middle of 2000s, benefiting from next-generation sequencing, cancer genomics flourished and promoted the launch of large-scale tumor sequencing initiatives, such as The Cancer Genome Atlas (TCGA) in 2006 and the International Cancer Genome Consortium (ICGC) in 2007. The TCGA consortium published its Pan-Cancer Analysis of Whole Genomes (PCAWG) data in