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Our research group is working toward the development of novel antifungal peptides based on a natural model of peptide histatin-5. Histatin-5 is found in human saliva and known to protect our body against oral infections by Candida species. Candidiasis, or an infection caused by Candida species, is considered one of the most medically important fungal infections worldwide. Blood stream infections caused by Candida species are the fourth leading cause of hospital-acquired fungal infections that is associated with high mortality rates and high costs of treatment. This study investigated the modes of action of histatin-5 with the use of one 16-mer derivative lacking eight amino acids from the N-terminus of the native histatin-5 and three enantio, retro and retroenantio 16-mer analogs. All four derivatives showed significant fungicidal activity with Candida albicans via mechanisms independent of SSA2p hypothesized to be the histatin-5 receptor on the plasma membrane of C. albicans. All four derivatives were shown to target artificial yeast phospholipid membranes and their killing activities involved the electron transport chain or respiration of the yeast cells. The data obtained from this study suggested the existence of a short five amino acid sequence within the 24-residue sequence of histatin-5 peptide that may have fungicidal properties. Several novel peptides were generated by the dimerization of the 5-mer amino acid sequence and these peptides were shown to have strong antifungal activities. In vitro assays were used to investigate potential toxicity of the new antifungal peptides to mammalian cells and these peptides were shown to be nontoxic to NIH3T3 murine fibroblasts and sheep red blood cells at concentrations up to 100 microM. The testing of acute toxicity and immunogenicity of some of these peptides in mice was also performed to obtain data on the in vivo tolerance of animals. The results of this work are presented in the following chapters of this dissertation.