Blood culture contamination represents a source of frustration for clinicians and microbiologists. Contaminated cultures lead to diagnostic uncertainty and are associated with increased health care costs due to unnecessary treatment and testing. Several strategies have been investigated to decrease contamination rates and numerous approaches to distinguish between clinically significant bacteremia and contamination have been explored. In this review, an overview of blood culture contamination is provided and the potential utility of a variety of approaches to improve both detection and prevention is discussed. Multidisciplinary efforts and multitargeted strategies are required to improve the quality and reliability of blood culture sampling.