Although deregulated expression of microRNAs (miRNAs) demonstrably contributes to the development and progression of all types of human cancers, little data are available about the changes in miRNA expression levels in malignant melanoma. In our study, we performed microarray-based miRNA profiling of melanocytes and melanoma cell lines derived from either primary tumors or metastatic melanomas. In addition, we analyzed miRNA expression patterns of melanoma cell clones in which the expression of melanoma specific genes was stably knocked down by antisense techniques. We also generated miRNA expression profiles for two derivatives of a melanoma cell line that differ in their invasive potential. Comparing miRNA expression patterns of melanocytes and subsets of melanoma cell lines, we identified large cohorts of miRNAs associated with malignant transformation as well as with the progression of the disease and with metastatic colonization. Surprisingly, the bulk of miRNAs that deregulated most strongly was not described to be of importance in tumor development before. The results of our study, therefore, not only provide insights into alterations in the miRnomes of melanocytes and melanoma cell lines during melanoma progression but also present a large assortment of miRNAs to be analyzed for their potential as diagnostic markers or targets for therapies in the future.