A forward chemical genomic screen was carried out using Xenopus laevis embryos to identify compounds disrupting pigmented cell development, including the retinal pigment epithelial (RPE) layer of the eye and the melanophores (melanocytes). Phenotypes showing changes in cell migration, morphology and pigmentation were observed. The screen also identified compounds affecting other aspects of Xenopus development including general patterning and morphogenesis, eye development and edema formation. Evidence is presented for the molecular targets of three of the compounds identified. Xenopus melanophore and human melanoma cell lines were also utilised in follow-up cell morphology assays. Chemical genomic screens of this type have an important role to play in the identification of novel compounds providing new molecular tools, and biological information, along with identification of new protein targets and leads for potential therapeutic agents.