Intracellular PIP3, one of the inositol phospholipids, is closely related to carcinogenesis. In this study, we used melanoma mice lacking the Inpp4b gene, which was recently found to be involved in PIP3 production, to examine whether the malignancy of melanoma becomes more progressive as the amount of intratumoral PIP3 increases (PIP3 threshold model). The results suggest that Inpp4b heterozygous deleted melanomas are more malignant and resistant to treatment than Inpp4b homozygous deleted melanomas.