The Shox2 transcriptional regulator is known for its pleiotropic functions during mouse embryogenesis and is essential for cardiac pacemaker differentiation and consequently embryonic survival. At the genomic level, the Shox2 gene is flanked by an extensive gene desert spanning more than 500 kilobases and encoding a multitude of putative cis-regulatory elements (CREs) with distinct tissue-specific signatures. However, the transcriptional enhancer potential of the majority of these CREs, as well as the biological necessity of the gene desert as a whole, remained elusive. Using transgenic reporter assays and 4C-seq chromatin conformation capture in mouse embryos to validate elements with stringent epigenomic enhancer signatures, we identify a significant number of gene desert enhancers with distinct tissue-specific activities in Shox2 expressing tissues. Leveraging CRISPR/Cas9 to delete 580kb of the gene desert in the mouse genome, we demonstrate a requirement for this large regulatory domain in controlling embryonic survival and pleiotropic Shox2 expression, directly related to the identified enhancer activities. While transcription of Shox2 in the embryonic limb remained only moderately affected by the gene desert loss, its expression in craniofacial and cardiac domains was severely reduced. Remarkably, in embryos lacking the gene desert, Shox2 expression in the sinus venosus was abolished, resulting in embryonic lethality due to the absence of Shox2 in cardiac cells with pacemaker signature. Finally, using ATAC-seq in embryonic hearts to expand cardiac enhancer predictions, we discovered a sinus venosus-specific enhancer region located in the gene desert, and potentially acting as a substrate for regulation of the cardiac pacemaker system and embryonic viability. In summary, our results identify a gene desert indispensable for pleiotropic patterning and embryonic survival, and highlight differences in the cumulative activities of tissue-specific enhancers.