During the past two decades, there have been important advances in blood culture methodology. These advances have resulted in earlier detection and identification of pathogens causing bloodstream infections. However, there are many facets of the blood culture as a diagnostic test that are not affected by new culture methods or systems that continue to cause problems with interpretation of results. The objective of this review is to focus on those factors influencing the results of blood cultures that have clinical relevance. Such factors include skin preparation, timing, procurement techniques, volume of blood obtained, number of cultures, anaerobic blood cultures, and contamination. In addition, bacteremia prediction models are discussed and suggestions are provided as to how these models could be of greater clinical use. Blood culture methods and systems are not discussed in this review.