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Recent developments in somatic mutation analyses have led to the discovery of codon-context targeted somatic mutation (TSM) signatures in cancer genomes: it is now known that deaminase mutation target sites are far more specific than previously thought. As this research provides novel insights into the deaminase origin of most of the somatic point mutations arising in cancer, a clear understanding of the mechanisms and processes involved will be valuable for molecular scientists as well as oncologists and cancer specialists in the clinic. This review will describe the basic research into the mechanism of antigen-driven somatic hypermutation of immunoglobulin variable genes (Ig SHM) that lead to the discovery of TSM signatures, and it will show that an Ig SHM-like signature is ubiquitous in the cancer exome. Most importantly, the data discussed in this review show that Ig SHM-like cancer-associated signatures are highly targeted to cytosine (C) and adenosine (A) nucleotides in a characteristic codon-context fashion. This review also provides an evidence-based model explaining how deaminases that cause mutations in cytosine and adenosine can gain access to their respective target motifs in genomic DNA (C-sites) and RNA (A-sites). It also highlights the clinical importance of understanding the molecular processes underpinning deaminase targeting for the development of new genomic diagnostics and drug discovery for pre-cancerous and clinically diagnosed cancer patients.