STAT (signal transducer and activator of transcription) family transcription factors are critical regulators of the development and differentiation of many cell types. STAT isoforms are generated by alternative splicing, but have also been suggested to be generated post-transcriptionally. In this issue of the Biochemical Journal, Schuster and colleagues have identified cathepsin G as the protease that cleaves full-length STAT5 (STAT5alpha) to generate a C-terminally truncated form in immature myeloid cells. However, the authors argue that this proteolytically generated isoform does not occur naturally in vivo; rather, it is artificially generated by cathepsin G during the preparation of cell extracts. This new evidence calls into question the physiological significance of this putative isoform and forces the general re-examination of proteolytically generated STAT isoforms.