There is an increasing world-wide demand for skin lightening active ingredients. Many common lightening ingredients on the market are either unsafe or ineffective at low concentrations. We therefore screened a series of hydroxy-stilbene derivatives for tyrosinase inhibitory activity. By chemical synthesis, the structures were optimized for efficacy and stability. The final candidate, 4-(1-phenylethyl)1,3-benzenediol, was found to be stable and to inhibit mushroom tyrosinase 22 times more effectively than kojic acid. In an assay with B16V melanoma cells, 4-(1-phenylethyl)1,3-benzenediol was the most potent inhibitor of melanin synthesis with an IC50 of 2 μM among the compounds investigated. The lightening effect of 4-(1-phenylethyl)1,3-benzenediol was not due to cytotoxicity as proved by an MTT assay on B16V cells. On pigmented 3D epidermis models, 0.1% of 4-(1-phenylethyl)1,3-benzenediol led to an almost complete suppression of melanin synthesis after 14 days of incubation. Finally, an in vivo test on Asian subjects proved that 4-(1-phenylethyl)1,3-benzenediol efficiently lightens human skin at 0.5% dosage. Optimal results are achieved when 4-(1-phenylethyl)1,3-benzenediol is applied in formulations with low oil content. In summary, we have demonstrated that 4-(1-phenylethyl)1,3-benzenediol is a potent, stable and safe skin lightener.