Abstract: With the widespread clinical application of azole antifungal agents, fungal drug resistance has become increasingly prominent, emerging as a critical challenge restricting the therapeutic efficacy of fungal infection therapy. This review systematically summarizes the research progress on the resistance mechanisms of azole antifungal agents, focusing on four core resistance mechanisms: mutations and overexpression of the drug target sterol 14α-demethylase, activation of ATP-binding cassette superfamily transporters/major facilitator superfamily transporter efflux pumps, cell membrane remodeling, and metabolic pathway reprogramming. It comprehensively outlines the current main strategies for combating fungal resistance, including drug repurposing, molecular structure optimization, development of targeted drug delivery systems, and mechanism-based combination therapy regimens. Furthermore, it categorically introduces anti-resistant azole drugs that are already on the market, in clinical trials, and in preclinical research, with a focus on analyzing the anti-resistance advantages and application prospects of novel azole derivatives. This review aims to provide references for the rational clinical selection of antifungal agents and the optimization of treatment regimens for resistant infections, as well as to offer insights and theoretical bases for the research and development of novel anti-resistant azole drugs.