Abstract Next generation sequencing (NGS) technology has revolutionized the world of molecular biology, genetics, and genomics by the integration of genome technologies with other research fields, essentially bringing genome center capacity to individual research laboratories. The requested instrument, the Illumina HiSeq 4000, is the latest next generation sequencer that will replace and supplement our older instruments that are becoming obsolete or at the end of their development life, and to offer competitive pricing due to its higher throughput and lower per base cost. This new instrument will empower groups at Baylor College of Medicine (BCM) from a broad range of disciplines who conduct research to understand the molecular mechanisms of human diseases, including disease gene cloning, cancer, gene expression, splicing, development and differentiation, and epigenetics. The shared Illumina HiSeq 4000 next generation sequencer will be placed at and administrated by the BCM Genomic and RNA profiling Core (GARP) to ensure smooth operation and easy access school-wide. Most importantly, the Illumina HiSeq 4000 retains all of the flexibilities of our current HiSeq 2500 and HiSeq 2000 machines, but is capable of generating more than twice as much sequence data per run in about one third of the time. In addition, as the Illumina HiSeq 4000 has adopted patterned flow cells, it can handle large variations in cluster density, which is a major challenge and common source of failures of our current models. We anticipate that the new instrument will reduce the failure rate, minimize sample repeat, and increase data generation by at least two fold. We will apply the system to a broad range of applications, including: 1) identifying direct downstream targets of transcription factors by ChIP-Seq; 2) performing transcriptome analysis of human tissues and model organisms by RNA-Seq; 3) identifying and cloning human disease genes by whole genome, whole exome, and targeted capture deep sequencing; 4) investigating alternative splicing and human diseases by splice junction sequencing; 5) examining effects of environment and nutrition on pregnancy, development, and disease by examining the epigenome through whole genome bisulfate sequencing and histone modifications; and 6) single cell DNA and RNA profiling. We have identified 18 participating groups whose research projects are highly diverse and are funded by eleven institutes at NIH, including NICHD, NIDDK, NEI, NCI, NIGMS, NHLBI, NIAMS, NHGRI, NINDS, NIAID, and the NIH director's office. As the participating PIs are all engaged in both basic and clinical research, we believe the introduction of this new NGS instrument will have direct, broad, and immediate impact on many medically relevant fields.