Extracts of the sponge genus Candidaspongia showed selective cytotoxicity toward melanoma cells in the NCI 60-cell-line screen. Continued investigation of the Candidaspongia sp. extracts led to the isolation of three new tedanolide analogues, precandidaspongiolides A (1) and B (2) and candidaspongiolide B (4), as well as candidaspongiolide A (3) and tedanolide (5). Semisynthetic derivatives were also generated to develop SAR. Candidaspongiolides A/B were the most potent and showed low nanomolar activity against several melanoma cell lines.