In an effort to optimize antifungal concentration at the infection site while minimizing the consequences of systemic administration, antifungals are often administered in a variety of unconventional methods, including aerosols, irrigations, topical administration, local administration, or the use of antifungal-impregnated beads or orthopedic cement. Most reports involve administration of amphotericin B. More recently, select azoles and echinocandins have also been administered. Data are emerging for the use of aerosolized formulations of amphotericin B in the prevention of invasive aspergillosis in high-risk patients. Use of antifungal-containing irrigating solutions (usually amphotericin B) most frequently involves their use as bladder irrigations (for the treatment of funguria), peritoneal lavage fluid (for management of fungal peritonitis), and nasal solutions (for the treatment of fungal sinusitis). Among these indications, amphotericin B bladder irrigations and nasal solutions are perhaps the best-studied. Most cases involve treatment in patients who are refractory to conventional therapy and/or have or are receiving systemic therapy concomitantly. Adequately controlled clinical studies to support the use of novel methods of antifungal drug administration are lacking for most indications. Thus, it is often difficult to determine the contribution of the novel antifungal in the treatment outcome.