Genotoxicity is described as the potential of xenobiotics to cause DNA damage by resulting in changes in the structure or information in genetic material. In addition, the formation of reactive oxygen species (ROS), which are by-products of oxidative respiration within the cell, Fenton reactions, and oxidative stress also cause DNA damage. Damage to biomolecules such as lipids, proteins, and DNA due to oxidative stress paves the way for the formation of many chronic diseases, especially cancer. In vitro, in vivo, and in silico models are used to detect all agents, including chemical and physical agents, that cause genetic damage and to evaluate their genotoxic potential. DNA damage that causes genotoxicity is frequently investigated in cancer and its treatments because it causes physical or chemical changes in DNA in cells that affect the interpretation and transmission of genetic information. Carcinogenesis is a process that includes the malignant transformation of cells after exposure to xenobiotics, changes in genome integrity due to gene mutations and chromosome damage, and eventually cancer development. This relationship between genotoxicity and cancer is particularly important for preclinical safety assessment of drugs and chemicals. It has also been reported that environmental and occupational exposure may cause genotoxic damage and pose a risk for cancer. This chapter aims to evaluate the mechanism of genotoxicity and cancer and the relationship between them, and the in vitro and in vivo studies conducted in this field.