The most predominant opportunistic fungal pathogens Candida sp, Aspergillus and Cryptococcus sp are emerging as a global problem of great concern as it is associated with increased morbidity and mortality. Although there are different classes of approved antifungal agents like polyenes, pyrimidines, azoles, and echinocandins, the morbidity and mortality rate due to systemic infection remains high, due to its toxicity, narrow spectrum of activity and tolerability. The continuous usages of these drugs are associated with resistance development and thus this is another area of emerging global problem. In addition, biofilm formation by fungal pathogens are proven to be an important virulence factor and are resistant to host defense mechanism and antifungal agents. Combination therapy has shown to be a promising choice to overcome the emergence of drug resistance, minimizing the toxic effects by reducing the drug dosage, and to increase the spectrum of killing. In this chapter, we have reviewed the last 5 years’ developments made in combinational antifungal therapy with special emphasize on biofilm related infections and have presented a reappraisal of the current practices associated with immunotherapy to treat fungal infections and future challenges.