Increased glycolysis resulting in local acidification is a hallmark of cancer. However, the mechanisms by which this acidification affects cellular behaviors such as migration are not understood. We report the discovery of Ogremorphin (OGM) a first in class inhibitor of GPR68 in a phenotypic zebrafish screen. The target of OGM was identified through a cheminformatics and receptor profiling, and validated genetically with knock down technology. GPR68 plays a critical role in neural crest development during zebrafish development. Furthermore, hiPSC derived Neural crest stem cell migration is inhibited by OGM. GPR68 is proton sensitive GPCR that is maximally active at ~pH6.6, and is upregulated in melanoma cell lines. We show that melanoma are more motile in acidic media. Furthermore, the increased migratory capacity is attenuated by OGM, which attenuates the formation of focal adhesions complexes. Taken together, the data suggests that pH mediated signaling is a critical component during embryonic development, and that GPR68 represents a possible novel pharmacological target for melanoma metastasis.