Technical Abstract: Kahalalide F shows remarkable anti-tumor activity against different carcinomas and has recently completed phase I clinical trials and is being evaluated in phase II clinical studies. The antifungal activity of this molecule has not been thoroughly investigated. In this report, we focused on acetylation and oxidation of the secondary alcohol of threonine, as well as reductive alkylation of the primary amine of ornithine and each product was evaluated for improvements in antifungal activity. Kahalalide F and analogs do not exhibit antimalarial, anti-leishmania, or antibacterial activity, however the antifungal activity against different strains of fungi, was particularly significant. This series of compounds was highly active against Fusarium spp. which represents an opportunistic infection in humans and phytopathogen. The in vitro cytotoxicity for the new analogs of Kahalalide F was evaluated in the NCI 60 cell panel. Analog 5 exhibited enhanced potency in several human cancer cell lines relative to Kahalalide F.