‘Rule out sepsis’ may be the most common discharge diagnosis among infants admitted to the neonatal intensive care unit. Although the frequency of sepsis, meningitis, and other confirmed bacterial infections has remained constant (between 1 and 5/1000 live births) for many years, the number of infants evaluated and treated is much higher. Each year in the United States, as many as 600 000 infants experience at least one evaluation for suspected bacterial infection during the birth hospitalization. The number treated is estimated at 130 000 to 400 000 per year. Despite massive overtreatment, delayed diagnosis still occurs. The Kaiser Permanente Medical Care Program (KPMCP) considers developing and implementing an evidence-based approach to ‘rule out sepsis,’ a research and operational priority. To achieve these goals, it is essential to consider two key aspects of the problem. First, it is important to adopt a phenomenologic approach that takes clinicians’ personal experience into account. This must include reflection on those aspects of experience often considered ‘irrational’ or ‘subjective.’ Second, incorporation of a phenomenologic approach needs to be tempered with sound epidemiologic methods. If one considers these two aspects-physician experience and sound epidemiology-it is clear that much of the existing literature on ‘rule out sepsis’ is of limited utility. Consequently, the KPMCP has conducted its own studies. These are aimed at characterizing the ‘sepsis work-up,’ developing electronic datasets that would permit clinicians to simulate various strategies, and developing techniques for ongoing electronic monitoring. This article summarizes the approach taken by the KPMCP Division of Research. It describes the results of a pilot study as well as the development and use of a dedicated neonatology outcomes database, the Kaiser Permanente Neonatal Minimum Data Set (NMDS). The NMDS database includes the Score for Neonatal Acute Physiology and permits ongoing monitoring of sepsis ‘work-ups’ as well as confirmed cases of neonatal infection. The article also describes how the experience from the pilot as well as the NMDS was incorporated in the design of a much larger study on ‘rule out sepsis.’ Finally, the article describes some important theoretic issues affecting decision rule development and the use of computer simulations in neonatology. These issues are 1) how one handles possible overanalysis of a dataset; 2) how one handles data points that are unstable (eg, the absolute neutrophil count, which can vary considerably depending on age and sampling conditions); and 3) the limitations of decision rules based on computer simulations.