Histatins (Hsts) are histidine-rich peptides exclusively present in the saliva of higher primates. In this study, we explored the effects of Hsts on cell-substrate and cell-cell adhesion. Histatin (Hst)-1 caused a significant (>2-fold) increase (EC50 = 1 µM) in the ability of human adherent cells to attach and spread, even in conditions that impaired cell spreading. Other tested Hsts did not stimulate cell spreading, indicating a specific effect of Hst1. The effect of Hst1 on cell-cell adhesion was investigated by using transepithelial resistance (TER) measurements in the human cell line Caco-2, a widely used model for the epithelial layer. We found that 10 µM Hst1 caused a 20% increase in TER compared to the negative control, indicating a function for Hst1 in intercellular cell adhesion and epithelial integrity. A role for Hst1 in both cell-substrate and cell-cell adhesion is highly conceivable, because these 2 modes of adhesion are closely related via shared components and connected signaling pathways.