p53 activity is orchestrated by a sophisticated combinatorial network of post-translational modifications (PTMs), which fine-tune protein stability, DNA binding affinity, subcellular trafficking, co-regulator assembly, and downstream transcriptional output. Beyond well-characterized phosphorylation and acetylation, an expanding repertoire of PTMs including methylation, ubiquitination, ubiquitin-like conjugation, and metabolism-coupled modifications constitutes a context-dependent PTM code that dictates p53-driven biological outcomes. This modification code governs chromatin engagement, DNA repair fidelity, transcriptional target selectivity, and diverse cell-fate programs in both wild-type and hotspot-mutant p53. A major conceptual advance in the field is the appreciation that p53 function arises not merely from individual modification events, but from dynamic PTM-PTM crosstalk mediated by dedicated PTM writers, erasers, and reader proteins. In this review, we synthesize current knowledge of p53 PTM-dependent regulatory circuits, allele-specific mutant p53 gain-of-function biology, and emerging translational opportunities. We further discuss outstanding bottlenecks limiting clinical translation of PTM-targeted strategies across wild-type and mutant p53-driven cancers.