Mycochemical study of the mushroom Gymnopus fusipes led to the discovery of two new cyclopeptides. The two compounds, named as gymnopeptides A and B, are unprecedented highly N-methylated cyclic octadecapeptides. Detailed spectroscopic studies, Marfey's analysis, and a preliminary molecular modeling study suggested that both are natural cyclic β hairpins. The isolated compounds exhibited striking antiproliferative activity on several human cancer cell lines, with nanomolar IC50 values.