TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli and upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. P53 is the most frequently mutated gene in tumors with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) which promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for 1) boosting p53 activity in cancer, 2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, 3) targeting p53 in immunotherapy, and 4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.