The fungal infection caused by Cryptococcus neoformans is accountable for more than 220,000 deaths per year, worldwide. Antifungal drug resistance along with emerging incidents of invasive fungal infections has led to an urge for the development of potent antifungal drugs, which are possibly lesser prone to resistance. Cationic antimicrobial peptides provide a suitable alternative to the conventional antibiotics due to their cationic and amphipathic nature, which facilitate their binding and insertion to the fungal cell eventually leading to its death.1-3 Herein, we report His(2-aryl)-Trp-His(2-aryl) class of ultrashort amphipathic peptides. Histidine is known to display peculiar buffering properties at physiological pH besides its amphiphilic nature.4 Therefore, structural modifications in the histidine residues, at the C-2 position,5 in the His-Trp-His based motif rationalize the alteration in amphipathicity of the peptides, resulting in altered bioactivity. A series of peptides were synthesized by varying the aryl group at the C-2 position of L-histidine. The most active peptide exhibited two times better in vitro activity than amphotericin B against C. neoformans with an IC50 value of 0.35 μg/mL, in addition to high proteolytic stability and no apparent cytotoxicity. The mechanistic investigations were executed by electron microscopy, which revealed it to act through a multistep process involving membrane permeabilization, cell wall and plasma membrane disruption, interaction with intracellular components of the cell, ultimately leading to cell death. The amphipathic character of rationally modified histidines, short peptide sequence, high proteolytic stability, lack of cytotoxicity and membrane-specific action prove this series of compounds as an attractive alternative candidate for antifungal drug discovery.