Cancer therapies have attempted to target the transcription factor p53, a gene also described as the “guardian of the genome,” for decades. However, the approach has faced numerous barriers to clinical efficacy due to several factors: mutations in p53 occur in almost half of all human cancers, mutations are cancer-specific, and the associated genomic changes grant mutant p53 with oncogenic potential unique from that of wild-type p53. A host of new therapeutic agents have emerged that work to target mutant p53. These agents can broadly be classified into six categories: the viral approach, direct modifiers of the p53 pathway, epigenetic modifiers of the p53 pathway, synthetic lethal agents, structural reactivators, and immune activating vaccines. Even these strategies have been met with limited success. Bypassing p53 entirely may be the next avenue in cancer therapeutics to kill tumor cells regardless of p53’s mutation pattern.