Variant alleles of the human MC1R gene are strongly associated with red hair color, fair skin and poor tanning ability (RHC-trait). Recently, we demonstrated that melanocytes harboring RHC-associated alleles have markedly reduced surface expression and/or impaired G-protein coupling of the corresponding receptor protein. The consequences of such a deficit on MC1R-mediated signaling pathways have now been quantitatively evaluated utilizing strains of human primary melanocytes homozygous for RHC-associated variant alleles and comparing responses to wild-type strains. The ability of melanocortin peptides to increase transcription of cAMP-dependent pigmentation genes, including MITF and SLC45A2, was abrogated in melanocytes with RHC-associated variant alleles, an effect that may contribute to the RHC phenotype. Activation of the c-Fos transcription factor gene was also severely compromised, a finding of potential relevance for non-pigmentary roles of MC1R. We also confirmed p38 signaling as an MC1R-regulated pathway and identified a large synergistic interaction between UV irradiation and MC1R stimulation for the activation of p38. This synergism was impaired in melanocytes expressing RHC variants of MC1R which may be relevant for the poor tanning ability associated with individuals possessing these alleles.