The c-myc oncogene acts as a pluripotent modulator of transcription during normal cell growth and proliferation. Deregulated c-myc activity in cancer can lead to excessive activation of its downstream pathways, and may also stimulate changes in gene expression and cellular signaling that are not observed under non-pathological conditions. Under certain conditions, aberrant c-myc activity is associated with the appearance of DNA damage-associated markers and karyotypic abnormalities. In this chapter, we discuss mechanisms by which c-myc may be directly or indirectly associated with the induction of genomic instability. The degree to which c-myc-induced genomic instability influences the initiation or progression of cancer is likely to depend on other factors, which are discussed herein.