A patient with metastatic cutaneous melanoma responsive to immunotherapy experienced several recurrences over a decade of observation. With each recurrence, biopsies were obtained and cell lines generated. A rare mutation of the beta-catenin gene and an unbalanced methylation of the androgen receptor were documented in all cell lines. Karyotyping and comparative genomic hybridization identified consistent genetic traits in spite of divergent phenotypes, suggesting that all the metastases were derived from the same primary tumor, although they were each probably not derived from the most recent previous metastasis in a sequential manner. Thus, metastatic melanoma recurs from a common progenitor cell and phenotypic changes occur around a central core of genetic stability. This observation may bear significance for the development of targeted anticancer therapies.