The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes, including cell cycle arrest, apoptosis, senescence, DNA repair, and metabolic regulation. In response to diverse stresses, p53 undergoes multiple posttranslational modifications (PTMs) that coordinate with intimate interdependencies to precisely modulate its diverse properties in given biological contexts. Notably, PTMs can recruit ‘reader’ proteins that exclusively recognize specific modifications and facilitate the functional readout of p53. Targeting PTM–reader interplay has been developing into a promising cancer therapeutic strategy. In this review, we summarize the advances in deciphering the ‘PTM codes’ of p53, focusing particularly on the mechanisms by which the specific reader proteins functionally decipher the information harbored within these PTMs of p53. We also highlight the potential applications of intervention with p53 PTM–reader interactions in cancer therapy and discuss perspectives on the ‘PTMomic’ study of p53 and other proteins.