Drotrecogin alfa (activated) is a new agent that may substantially affect the treatment of patients with severe sepsis. Despite its therapeutic promise, treatment with drotrecogin alfa (activated) represents a new challenge for many clinicians and health care centers. Specifically, optimizing the appropriate role for drotrecogin alfa (activated) requires balancing numerous issues, including its efficacy in high-risk patients with its potential for indiscriminate administration. One common approach to minimizing indiscriminate administration of drotrecogin alfa (activated) and maximizing its efficacy while minimizing its toxicity is for hospitals to develop therapeutic guidelines that define how the agent should be used. We outline factors that should be considered when developing drotrecogin alfa (activated) therapy guidelines and address realistic questions that routinely arise in clinical practice regarding the implementation of such guidelines and the administration of this product. In general, the guidelines must facilitate optimization of drug therapy and not be viewed as hurdles to drug therapy. Developing clear guidelines that are based on evidence, outlining a specific process to facilitate optimal therapy, and educating all parties involved are paramount to ensuring that the benefits of therapy are maximized.