Research into the molecular genetics of uveal melanomas (UM) has identified several predictors of metastatic disease as well as signaling pathways and molecules that can be targeted using systemic therapies. Most UM have GNAQ/11 initiating mutations, which activate the MAPK signaling pathway, with dysregulation of the PI3K/AKT and others pathways. Some patients develop UM because they have the BAP1 tumor predisposition syndrome, which also causes malignant mesothelioma and renal cell carcinoma. Metastasis is associated with many genetic aberrations, particularly chromosome 3 loss, chromosome 8q gain, and somatic BAP1 mutation, whereas SF3B1 mutation predicts late metastasis, while chromosome 6p gain, and EIF1AX and CNKSR3 mutations are associated with a good prognosis. Data from The Cancer Genome Atlas (TCGA) indicate four prognostic groups of UM, categorized according to chromosome copy number variations, mutations, and DNA methylation profiles. Other abnormalities include PTEN inactivation, inhibition of the retinoblastoma (Rb) and p53 pathways, cyclin D1 dysregulation, CDKN2a promoter hypermethylation, and overexpression of preferentially expressed antigen in melanoma (PRAME). The latter, which occurs in 25% of UM, leads to genomic instability in these tumors. Several potential MAPK/MEK, PI3K/AKT targets for UM therapy have been identified, using mTOR inhibitors, tyrosine kinase inhibitors, c-Met pathway inhibitors, CXCR4 small molecule inhibitors, histone deacetylase inhibitors, and others. More recent therapies aim at harnessing the tumor microenvironment of metastatic uveal melanomas. For example, immunotherapies utilising bispecific T-cell receptor molecules that helps the body’s immune system identify and destroy uveal melanoma cells, is a strategy that is having some success with these aggressive tumors.