The rapidly expanding use of electronic records in health-care settings is generating unprecedented quantities of data available for clinical, epidemiological, and cost-effectiveness research. Several challenges are associated with using these data for clinical research, including issues surrounding access and information security, poor data quality, inconsistency of data within and across institutions, and a paucity of staff with expertise to manage and manipulate large clinical data sets. In this article, we describe our experience with assembling a data-mart and conducting clinical research using electronic data from four facilities within a single hospital network in New York City. We culled data from several electronic sources, including the institution’s admission-discharge-transfer system, cost accounting system, electronic health record, clinical data warehouse, and departmental records. The final data-mart contained information for more than 760,000 discharges occurring from 2006 through 2012. Using categories identified by the National Institutes of Health Big Data to Knowledge initiative as a framework, we outlined challenges encountered during the development and use of a domain-specific data-mart and recommend approaches to overcome these challenges.