Despite extraordinary gains in molecular therapies for melanoma, about half of all melanomas lack a “druggable” oncogene. One proposed approach for treating these therapeutically-orphaned tumors is by targeting transcriptional dependencies (“oncogene starvation”), whereby survival factors are depleted through inhibition of various transcriptional regulators. Considering the published success of MITF suppression through inhibition of CDK7, we sought to assess the utility of targeting CDK9, which regulates transcriptional elongation and which is being studied in various clinical trials. We undertook 2 strategies to inhibit CDK9- a PROTAC linked to thalidomide (THAL-SNS-032, TS-032) to rapidly degrade CDK9 and a selective CDK9 kinase inhibitor (NVP-2). We performed 2D cell viability studies using CellTiter-Glo luminescence in 2 uveal melanoma (UM), 1 triple-wild type melanoma (TWT), 6 BRAF and NRAS-driven melanoma, and 3 non-malignant fibroblast and melanocyte cell lines. At 500nM, both TS-032 and NVP-2 demonstrated greater suppression of UM and TWT melanomas with mean fractional survivals of 0.16 and 0.10, respectively, compared to 0.87 and 0.60 in BRAF/NRAS mutated melanomas (p = 0.0045 and 0.0005) and 0.64 and 0.77 in non-malignant controls (p = 0.0035 and 0.0009). The range of GI50 for TS-032 and NVP2 in UM and TWT was 23-107nM and 10-26nM compared to 300-1584nM and 96-130nM in BRAF/NRASmelanoma and 379-970nM and 742-2196nM in controls. These results were confirmed in a 3D culture system whereby cells were arranged in spheroids using Matrigel extracellular matrix and viability was visualized using operetta and LIVE/DEAD staining assay. Intracellular depletion of CDK9 was rapid (within 24 hrs). Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing melanomas which ostensibly lack single oncogenic drivers, such as UM and TWT tumors.