There is an increasing amount of clinical data in operational electronic health record (EHR) systems. Such data provide substantial opportunities for their re-use for many purposes, including comparative effectiveness research (CER). In a previous paper, we identified a number of caveats related to the use of such data, noting that they may be inaccurate, incomplete, transformed in ways that undermine their meaning, unrecoverable for research, of unknown provenance, of insufficient granularity, or incompatible with research protocols. In this paper, we provide recommendations for overcoming these caveats with the goal of leveraging such data to benefit CER and other health care activities. These recommendations include adaptation of "best evidence" approaches to use of data; processes to evaluate availability, completeness, quality, and transformability of data; creation of tools to manage data and their attributes; determination of metrics for assessing whether data are "research grade"; development of methods for comparative validation of data; construction of a methodology database for methods involving use of clinical data; standardized reporting methods for data and their attributes; appropriate use of informatics expertise; and a research agenda to determine biases inherent in operational data and to assess informatics approaches to their improvement.