Big Data in healthcare promise to answer real world questions that can be difficult to address with randomized clinical trials. In this perspective article, we analyze five current Big Data informatics challenges of (1) data volume, (2) research oversight by Institutional Review Boards, (3) semantic data integration (4) data formats, and (5) access to knowledge bases from a biomedical informatics perspective. After briefly describing each challenge, we discuss examples of how are being addressed today. With the ever increasing number of Big Data healthcare repositories, the emphasis is shifting from mere data aggregation to advanced data transformation and analysis.