Uveal melanoma is the most common primary intraocular tumor in adults and exclusively disseminates haematogenously in order to form metastases. The aim of this study was to measure the transcriptional profiles of human uveal melanoma cells isolated from a primary intraocular tumor, circulating malignant cells (CMCs), and metastases in order to elucidate the changes in gene expression associated with this progression. Human EST microarrays and universal reference RNA were used to measure the differences between tissue samples isolated from an immunosuppressed xenograft rabbit model of uveal melanoma. Cells were isolated from a single rabbit at the time of sacrifice from an intraocular tumor, peripheral blood, and metastasis. RNA was extracted from each sample and subjected to transcriptional profiling analysis. Results were compared to the transcriptional profiles previously obtained from the original cell line used for intraocular injections. Changes were verified using real-time PCR analysis. A total of 314 significant changes in gene expression were seen from the intraocular tumor to metastasis, as determined by transcript abundance. Principle Components Analysis was used to cluster these changes into four distinct groups. An additional 61 statistically significant changes were observed between the recultured and CMCs, with the latter believed to represent an intermediate step in the progression from intraocular tumor to metastasis. In conclusion, we have produced a detailed analysis of the transcriptional changes that take place as human uveal melanoma cells evolve from a primary tumor to metastasis in a xenograft animal model, including the decrease in expression of specific melanoma markers.