Combination therapy with amphotericin B and flucytosine is considered to be the treatment of choice for cryptococcal infections. However, for other infections and combinations of antifungal infections, the data are less clear-cut. The concurrent use of amphotericin B with an azole has elicited controversy, given the potential of antimicrobial antagonism. The results of one recent candidemia study suggest that the potential antagonism may not be an issue; the combination of amphotericin B and fluconazole provided more effective clearance of Candida from the bloodstream than did fluconazole used alone. Several in vitro and animal studies have shown antagonism between the azoles and amphotericin B for aspergillosis. However, introduction of the new class of agents that target beta-glucan synthase (echinocandins) has invigorated the prospects of combination therapy. The echinocandins and polyenes are not antagonistic, and there is evidence that the echinocandins may provide additive to synergistic activity in combination with triazoles. For patients whose aspergillosis is progressing despite monotherapy, the addition of a second agent, such as an echinocandin, may be reasonable.