Malignant transformation of melanocytes frequently coincides with loss of E-cadherin expression. Here, we show that loss of E-cadherin leads to induction of nuclear factor kappa B (NFkappaB) activity in melanoma cell lines. Melanoma cells show constitutively active NFkappaB, whereas no activity is found in primary melanocytes. After re-expression of E-cadherin in melanoma cells, strong downregulation of NFkappaB activity was found. Consistently, NFkappaB activity was induced in primary human melanocytes after inhibition of E-cadherin activity by functionally blocking anti-E-cadherin antibodies. Interestingly, re-expression of E-cadherin-blocked p38 MAPK activity and the p38 MAPK inhibitors SB203580 and SB202190 almost completely prevented NFkappaB activation in melanoma cells. Furthermore, cytoplasmatic beta-catenin induced p38 and NFkappaB activation in malignant melanoma. To our knowledge, this is the first report suggesting a correlation between E-cadherin and NFkappaB activity in melanocytes and melanoma cells. In summary, we conclude that loss of E-cadherin and cytoplasmatic beta-catenin induces p38-mediated NFkappaB activation, potentially revealing an important mechanism of tumorigenesis in malignant melanomas.