Transcription factor p63 originates from p53 protein family and is encoded by TP63 gene. TP63 gene contains two different promoters encoding two proteins, TAp63 and ΔNp63, which can be cleaved to produce p63α, p63β, p63δ and some other subtypes. ΔNp63α is one of the promoters of TP63 gene and acts as a core regulatory factor to regulate gene expression at epigenetic and transcriptional levels. Recent research shows that ΔNp63α abnormal expression can lead to the occurrence of various malignant tumors and reduce the sensitivity of malignant tumors to radiotherapy and chemotherapy. Therefore, ΔNp63α can be used as a diagnostic marker and therapeutic target for malignant tumors. This article reviews the latest research progress of ΔNp63α in the mechanism and drug resistance in malignant tumors.