Background Angiosarcomas are a group of aggressive rare tumors of endothelial origin. The genomic landscape of the disease was recently characterized, identifying distinct subtypes defined by ultraviolet (UV) mutational signatures and human herpesvirus-7 (HHV-7) as possible aetiologies. Methods To further characterize the molecular events regulating angiosarcoma development, we investigated the epigenomic enhancer landscape using H3K27ac chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples (n=14) and their matched normal tissue where available (n=9). RNA-seq was also performed for tumor (n=16) and normal tissue (n=7) samples. Tumor (MO-LAS, ISO-HAS, ASM) and normal HDMEC cell-lines were similarly profiled. Results Unsupervised hierarchical clustering of H3K27ac signals at enhancers revealed global similarity between tumor samples, regardless of UV or HHV-7 status. Among the top ranking tumor-specific differentially-bound enhancers and expressed genes include PREX1, CCR1, LYN, PIK3R6, CSF2RB, CKAP2L, BCL2A1, HCK, RHOH and CXCL6. We focused on LYN, a potentially-druggable Src-family kinase. In keeping with initial observations, LYN was expressed higher in the tumor cell-lines by quantitative PCR and further validated on Western blot. Bafetinib, a known inhibitor of LYN kinase, was able to inhibit the viability of all tumor cell-lines in a dose-dependent manner at 72 hours (IC50 all between 5-10 μM), while decreasing protein expression of LYN and phospho-LYN. However, HDMEC cells were relatively resistant (IC50 > 10 μM). Finally, to investigate transcription factor-binding site enrichment, we analysed frequencies of cognate consensus DNA-binding motifs at super-enhancer regions using HOMER motif analysis and identified bZIP-domain and EST-domain transcription factors as candidate angiosarcoma regulators, including that of LYN expression. Conclusions We described the enhancer landscape of human angiosarcomas, highlighting LYN as a potential therapeutic target. Our preliminary analysis of potential transcription factor binding identified candidate transcription factors responsible for regulating LYN expression.