In this issue of JAMA Ophthalmology, 2 articles1,2 address important aspects of melanoma: pathogenesis (driver mutations), prognostication, and survival. Genetic alterations detected in the primary tumor by chromosomal tests (fluorescence in situ hybridization), DNA-based tests (single-nucleotide polymorphism and multiplex ligation–dependent probe amplification), and RNA-based tests (gene expression profiling) only reflect tumor determinants of metastases. It has been known for some time that uveal melanoma is not a localized disease, and with suitable techniques, circulating uveal melanoma cells can be detected in the peripheral blood.3 Other as-yet-unknown host defense factors (as detected by analysis of plasma proteins) also play a role.4 The study of mutational events in the samples of metastatic tumors to the liver will yield the missing pieces to complete the puzzle.5