Nine new cyclodepsipeptides, homophymines B-E (2-5) and A1-E1 (1a-5a), were isolated from the polar extracts of the sponge Homophymia sp. The new structures, featuring new polyketide-derived end groups, were determined by interpretation of NMR and MS data. The configurations of the new end groups was secured by the application of J-based configurational analysis. Homophymines displayed very potent antiproliferative activity (IC(50) in the nM range) against a panel of human cancer cell lines.