Gene regulation describes the totality of molecular events that result in precisely orchestrated gene expression patterns which collectively drive organismal development and define cellular states. Much of this logic is encoded in the genome itself, which is subject to mutation and natural variation. Because of the fundamental role that gene regulation plays in cellular biology, perturbations to gene expression patterns may have pathophysiological consequences, and these are far from being well understood. In my dissertation research, I used a variety of experimental and computational approaches to study the genetic basis of gene regulation in the context of normal cellular development and human disease. First, I developed an experimental approach to improve the ATAC-seq assay, a commonly used assay to detect regulatory elements. This approach uses CRISPR/Cas9 to remove contaminating mitochondrial DNA fragments, increasing the number of regulatory elements identified. Next, I investigated the gene-regulatory function of two ultraconserved enhancer elements in the mouse genome. I used CRISPR/Cas9 genome engineering to delete these elements from the germline and reported that deletion of one element caused a body weight phenotype, albeit in the absence of gene expression changes in the hypothalamus, challenging our view of these elements as traditional enhancers. Finally, I used promoter capture Hi-C in combination with gene expression profiling and publicly available epigenetic datasets to study the gene-regulatory changes that accompany human cardiomyocyte differentiation. I integrated these data with 50 genome-wide association study results for cardiovascular disease traits in order to prioritize target genes for functional follow up studies and provide a gene regulatory context to the thousands of loci associated with these diseases. Taken together, this work improved our ability to assay functional regions of the genome with experimental approaches, contributed further data to the function of ultraconserved elements, and increased our understanding of the complex nature of long-range gene regulation in the context of cardiomyocyte differentiation and cardiovascular disease.