From the endophytic fungus Pestalotiopsis sp. isolated from the leaves of the Chinese mangrove, Rhizophora mucronata, two novel hybrid sesquiterpene-cyclopaldic acid metabolites with an unusual carbon skeleton, named pestalotiopens A and B, were obtained, together with the already known phytotoxin altiloxin B. Pestalotiopen B even contains a third, triketide-derived module. The constitutions and the absolute configurations of the new metabolites and of altiloxin B were unambiguously determined by a combination of spectroscopic methods and quantum-chemical optical-rotatory dispersion (ORD) and circular dichroism (CD) calculations. A biosynthetic pathway to pestalotiopens A and B is proposed with altiloxin B as one of the suggested precursors. Pestalotiopen A shows moderate antimicrobial activity against Enterococcus faecalis. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.