The article discusses the causes and consequences of tumor heterogeneity, emphasizing the genetic and clonal aspects. It highlights that human cancers often display significant intra-tumor heterogeneity in various phenotypic features, such as cell surface receptors, proliferation, and angiogenic potential. This heterogeneity is attributed to both morphological and epigenetic plasticity, as well as the coexistence of genetically divergent tumor cell clones. The authors review evidence for both intra-tumor clonal heterogeneity and evolutionary divergence between primary tumors and metastatic outgrowths. They also discuss the potential biological and clinical implications of clonal heterogeneity, including its role in therapeutic resistance and the evolution of metastases. The article concludes by emphasizing the need for further research to understand the clonal relationship between primary and metastatic tumor cell populations, as this knowledge could inform therapeutic decisions and improve treatment outcomes.The article discusses the causes and consequences of tumor heterogeneity, emphasizing the genetic and clonal aspects. It highlights that human cancers often display significant intra-tumor heterogeneity in various phenotypic features, such as cell surface receptors, proliferation, and angiogenic potential. This heterogeneity is attributed to both morphological and epigenetic plasticity, as well as the coexistence of genetically divergent tumor cell clones. The authors review evidence for both intra-tumor clonal heterogeneity and evolutionary divergence between primary tumors and metastatic outgrowths. They also discuss the potential biological and clinical implications of clonal heterogeneity, including its role in therapeutic resistance and the evolution of metastases. The article concludes by emphasizing the need for further research to understand the clonal relationship between primary and metastatic tumor cell populations, as this knowledge could inform therapeutic decisions and improve treatment outcomes.