Many types of human cancers overexpress MDM2 protein. A common characteristic among these cancers is an associated increase in mdm2 splice variants. Provided here is a comprehensive list, based on a literature review, of over 70 mdm2 variants. These variants are grouped according to in-frame versus out-of-frame status and their potential (or ability) to be translated into isoform proteins. We describe the putative functions for these mdm2 splice variant mRNAs, as well as the mechanistic drivers associated with increased mdm2 transcription and splicing. The paradoxical signal transduction functions of the most commonly studied variants mdm2-a,-b and -c are addressed for their outcomes in the presence and absence of wild-type p53. These outcomes vary from tumor promotion to growth arrest. Finally, we present issues in the detection of endogenous MDM2 protein and how many of the antibodies commonly used to detect MDM2 do not present a full picture of the cellular representation of the isoform proteins. This review provides a focusing lens for individuals interested in learning about the complexities of mdm2 mRNAs and their protein isoforms as well as the roles MDM2 isoforms may play in cancer progression.