Bacterial biofilms and their role in disease have been investigated in detail over 15 to 20 years, but research on fungal biofilms has traditionally lagged. Although other fungal species have been associated with biofilm formation, this chapter concentrates on Candida albicans since it is the fungal system that has received the most attention to date regarding its biofilm-forming ability. Different mechanisms may be responsible for the intrinsic resistance of biofilms to antimicrobials. These include (i) effects of the biofilm matrix on penetration of drugs; (ii) decreased growth rate and nutrient limitation; (iii) expression of resistance genes, particularly those encoding efflux pumps; and (iv) presence of “persister” cells. Several studies have examined the effects of growth rate and nutrient limitation in relation to drug resistance in C. albicans. In addition, an intriguing observation is that anaerobic growth leads to high levels of antifungal drug resistance in C. albicans; this could contribute to the intrinsic resistance in cells within the biofilms, where oxygen limitation may occur. Importantly, multiple antifungal agents can be substrates for some of these transporters, and thus their overexpression leads to cross-resistance among different drugs. The biofilm mode of growth results in antifungal drug resistance and protection from host defenses, which carry important clinical repercussions. In addition, it is likely that biofilm infections involve bacteria and various Candida species in a polymicrobial consortium. In these complex communities, cell-cell communication, across both kingdom and species, may modulate gene expression, including drug resistance mechanism.