In human cancer, the role of genetic mutations, epigenetic alterations, and cellular repair mechanisms are becoming increasingly apparent. Recent studies have elucidated significant variations of the genetic codes that underpin cancer development in a variety of cancer subtypes. Genetic variations provide a backbone upon which cancer cells can adapt to overcome both intrinsic and extrinsic mechanisms designed to limit the growth of abnormal cells. This chapter provides an overview of the types of mutations, various epigenetic modifications, DNA repair mechanisms, and their relationship to the development of cancer, as well as various techniques utilized for the detection of these genetic alterations in cancer. With the development of new, advanced, and sensitive molecular techniques like next-generation sequencing and digital droplet polymerase chain reaction, our understanding of cancer biology is rapidly developing, and a critical appreciation and knowledge of these cancer-associated changes will likely lead to continued development of more effective therapies.