We recently found that treatment of normal human melanocytes (NHMs) with the antioxidant astaxanthin (AX) suppresses the stem cell factor (SCF)-stimulated protein expression levels of microphthalmia-associated transcription factor (MITF) at 1.5 h and of tyrosinase and endothelin B receptor at 96 h post-treatment. Analysis of the signaling cascade(s) involved revealed that although the major SCF-activated signaling cascade that leads to CREB activation (the c-KIT/Shc/Raf-1/ERK/RSK/CREB axis) is not interrupted, the increased phosphorylation of CREB is significantly abrogated by AX. We show for the first time that treatment of NHMs with SCF activates the p38/mitogen and stress-activated kinase (MSK1) axis in a c-KIT dependent fashion. Interestingly, whereas AX does not abrogate the SCF-induced activation of p38, it does affect the increased phosphorylation of its downstream target, MSK1. The lineage connection of p38/MSK1 activation with CREB activation and its associated MITF expression is supported by our finding that while silencing MSK1 abolishes the activation of CREB and the subsequent increase in total MITF proteins at 15 min and at 1.5 h, respectively, post-stimulation with SCF, inhibitors of p38 and of MSK1 abrogate the SCF-induced increase in total MITF proteins at 1.5 h post-stimulation. These findings suggest that SCF-stimulated melanogenesis can be abrogated by interrupting MSK1 phosphorylation, providing evidence for involvement of the p38/MSK1/CREB/MITF axis, providing new evidence for the ROS depletion independent interruption by antioxidants of SCF-triggered signaling.