Almost 50% of uveal melanoma patients develop metastatic disease despite successful ocular treatment. Metastases usually involve the liver and only rarely respond to treatment, so most patients die within a year of the onset of symptoms. There are hopes that systemic adjuvant therapy may delay or prevent metastatic disease. This requires targeting of high-risk patients according to anatomic, histologic, and genetic predictors. The metastatic disease occurs almost exclusively in patients whose tumor shows genetic aberrations such as chromosome 3 loss, chromosome 8q gains, a class 2 gene expression profile (GEP), increased preferentially expressed antigen in melanoma (PRAME) expression, and BAP1 mutation. The detection of lethal genetic aberrations has become more sensitive with the development of methods such as comparative genomic hybridization, microsatellite analysis, multiplex ligation-dependent probe amplification, single-nucleotide polymorphisms, gene expression profiling, next-generation sequencing, and immunohistochemical analysis of nuclear BAP1 expression. The time from ocular treatment to the onset of metastatic disease tends to be shorter in patients with a larger, more extensive, ocular tumor and a higher grade of malignancy as evidenced by epithelioid cytomorphology and higher mitotic count. Ideally, prognostication is performed by multivariable analysis using a tool such as the Liverpool Uveal Melanoma Prognosticator Online (LUMPO). Accurate prognostication enhances quality of life, especially in patients with a good prognosis. It also allows the targeting of systemic surveillance and systemic adjuvant therapy for high-risk patients and enhances opportunities for research.