Abstract Over the past quarter of a century, invasive fungal infections have emerged as an important cause ofmorbidity and mortality in immunocompromised patients. Although several new antifungal drugs havebeen licensed in recent years, antifungal drug resistance is becoming a major concern during treatment ofsuch patients. The resistance may be intrinsic, acquired or clinical. The understanding of the mechanismof resistance and clinical impact is important while planning treatment strategies. Four altered geneexpression pathways have been identified in azole resistance. The mechanism of resistance in polyene andechinocandins is still not clearly understood. Recent studies have revealed that molecular chaperone heatshock protein (Hsp90) can alter the relationship between genotype and phenotype leading to a profoundimpact on antifungal drug resistance. Though definite progress has been made to correlate standardizedin vitro antifungal susceptibility testing with prediction of treatment outcome, limitations still exist due totime required for testing and understanding the factors leading to clinical resistance. Overall, the level ofresistance to antifungal agents is still relatively low, but there is a possibility of antifungal resistancebecoming a crucial determinant of outcome following antifungal therapy in future.