For years, the two main isoforms of PTPN2 have been an interesting yet academic topic of debate for researchers working on this phosphatase. In recent years, several studies were published in which these isoforms were attributed specific functions. Most importantly, differences in their stoichiometry have been reported to be associated with certain diseases such as inflammatory bowel diseases (IBDs). Hence, understanding the evolutionary ontogeny of the main transcripts and the physiological consequences of their expression have now become clinically relevant issues. Herein we describe the genomic controls placed upon PTPN2, the identified splice variants, the encoded PTPN2 proteins, and both the known and putative post-translational modifications that have been reported. Moreover, we examine the expression of PTPN2 isoforms in specific tissues as well as in a disease setting. PTPN2 is an important negative regulator of inflammation. Therefore, the following protocols are effective approaches for its adequate monitoring in inflammatory diseases progression and outcome.