Over the past decade, the emergence of biofilm-related invasive fungal diseases has been the subject of numerous studies focused on antifungal resistance and its impact on antifungal therapy in severely ill patients. The majority of the studies investigated the molecular mechanisms involved in antifungal resistance and pathogenicity of biofilm production by Candida albicans and Aspergillus fumigatus, the most common etiologic agents of yeast and mold invasive infections. The main mechanism characterizing biofilm-related antifungal resistance is the production of extracellular matrix, a physical barrier preventing the drugs from entering and expressing their activity. However, over-expression of efflux pumps, genetic changes of drug targets, persister cells, biofilm-host immune system interaction, proteins leading to filamentation, all together contribute to the onset of biofilm antifungal resistance. Some of these mechanisms are shared with planktonic cells and are often related to developmental phases of biofilm formation. All physical and genetic factors leading to biofilm-related antifungal resistance have been briefly discussed.