Invasive fungal infections (IFI) parallel the explosive increase in the immunocompromized patient population, and are characterized by diagnostic difficulties and extreme mortality. Candidemia in a tertiary referral hospital in the Middle East confirms the current epidemiologic shift in this common blood stream pathogen towards non-malignancy cases (38%) and antifungal prophylaxis failure (20%), high presentation sepsis scores and attributable mortality (32%). Invasive aspergillosis (IA) is also associated with high mortality. Use of non-invasive computerized tomographic (CT) radiologic scanning linked to early administration of high dose liposomal amphotericin B (LAB) is associated with a reduced mortality of 9.5% compared to historical experience of 28%.Life threatening invasive aspergillosis also occurs in patients who are less obviously immunocompromized. Investigations may reveal subtle immune deficits which could place the patient at some risk for an invasive mycosis. Antifungal treatment used in combination with progenitor cell growth factors and gamma-interferon has proved successful in such situations of progressive fungal disease unresponsive to antifungal therapy alone. Pharmacologic remodeling of existing compounds by lipidisation reduces both the toxicity denominator and the efficacy numerator of the therapeutic index when compared to the parent drug. A comparative dose study of liposomal amphotericin B in aspergillosis has demonstrated equi-efficacy, generated debate over the ability of the controlled clinical trial to be capable of assessing antifungal efficacy, and illustrated that recovery from an invasive fungal infection may require maximum tolerated doses and immunomanipulation. Several new antifungal strategies are under clinical investigation. These include reformulating existing antifungals, exploitation of the growing knowledge of virulence factors to synthesize antagonists, immune reconstitution and immunoprotection. An interim analysis of an ongoing placebo controlled study of recombinant interleukin-11 to assess its efficacy in reducing sepsis in leukemia patients through prevention of chemotherapy induced gut epithelial cell apoptosis, has demonstrated a difference in the two study arms in sepsis rates and preservation of gastrointestinal epithelial cell integrity. The unique and special challenges presented by the dynamic epidemiologics of invasive fungal infections are demanding and attracting considerable responses, in the fields of diagnosis and therapeutics. Current strategies need considerable improvement, yet ongoing collaborative efforts will have a positive impact on our understanding of the fungus-host interaction and ultimately our ability to offer better care for our patients with invasive mycoses.