Introduction: For decades, p53 was researched as a single protein with alterations described as mutants. The discovery of 12 human p53 isoforms expressed from 9 transcripts changed this perception, eloquently explaining the numerous roles p53 plays, including apoptosis, senescence and regeneration. Area covered: Here we summarise the p53 isoforms and their relevance to cancer to establish an understanding and theorise on potential applications of the isoforms in clinical practice.