Current data indicate that caspofungin has in vitro activity against virtually all Candida species. However, we report herein a case of disseminated candidiasis due to Candida krusei which emerged during caspofungin treatment. Lung and brain secondary sites were then successfully treated using a combination of amphotericin B plus flucytosine, amphotericin B lipid complex, and voriconazole, sequentially. Among the total of four well documented cases of refractory invasive candidiasis during caspofungin therapy, the common risk factors appear to involve prior abdominal surgery, persistent foreign body, and anatomical sites where drug concentrations may be sub-optimal for Candida species with increased MICs. Caspofungin failure should be suspected in patients with persistent or emergent signs and symptoms of deep-seated invasive candidiasis.