Five sesquiterpenoids containing isonitrile or isothiocyanate groups were isolated from the sponge Acanthella klethra. Compounds 1 and 2 were identified as axisonitrile 3 and the corresponding isothiocyanate derivative, respectively. Compounds 3-5 were found to be eudesmane sesquiterpenes. None of these compounds was cytotoxic toward cultured KB-3 cells, but varying degrees of activity were observed with cultured Plasmodium falciparum. Compound 1 demonstrated greatest promise as an antimalarial agent.