Melanoma represents the deadliest form of skin cancer and originates from the pigment-producing melanocyte. The Microphthalmia-associated transcription factor (MITF) is indispensable for the establishment of fully differentiated melanocytes. Melanoma cells have been suggested to exploit the transcriptional activity of MITF to foster cancer progression. However, the role of MITF in regulating the formation of melanoma cells and to mediate metastasis is complex. The scope of this thesis was to study the impact of long term depletion of MITF in melanoma cell lines. Our findings revealed that MITF knock out (KO) melanoma cells exhibit reduced proliferation, migration and invasion potential compared to the control cell line. Transcriptomic analysis revealed a gain of extracellular matrix and neural crest related genes in MITF-KO cells, and, conversely melanocyte specific pigmentation genes were lost. Interestingly, the major components of focal adhesions, including Paxillin and Focal adhesion kinase were induced upon MITF depletion, thus explaining the phenotypic effects. Furthermore, the expression of the histone modifiers PRDM7and SETDB2was reduced in the MITF-KO cells. Consistently, the respective change in histone modification was observed in the promoters of genes that showed differential expression in MITF-KO cells. Together, we showed that the loss of MITF reprograms melanoma cells such that they lose proliferative capacity and gain expression of extracellular matrix and focal adhesion genes. This reprogramming is both due to direct effects of MITF itself but is also regulated by epigenetic modifiers that are under MITF regulation.