Bacteremia and sepsis are conditions associated with high mortality and are of great impact to health care operations. Among the top causes of mortality in the United States, these conditions cause over 600 fatalities each day. Empiric, broad-spectrum treatment is a common but often a costly approach that may fail to effectively target the correct microbe, may inadvertently harm patients via antimicrobial toxicity or downstream antimicrobial resistance. To meet the diagnostic challenges of bacteremia and sepsis, laboratories must understand the complexity of diagnosing and treating septic patients, in order to focus on creating algorithms that can help direct a more targeted approach to antimicrobial therapy and synergize with existing clinical practices defined in new Surviving Sepsis Guidelines. Significant advances have been made in improving blood culture media; as yet no molecular or antigen-based method has proven superior for the detection of bacteremia in terms of limit of detection. Several methods for rapid molecular identification of pathogens from blood cultures bottles are available and many more are on the diagnostic horizon. Ultimately, early intervention by molecular detection of bacteria and fungi directly from whole blood could provide the most patient benefit and contribute to tailored antibiotic coverage of the patient early on in the course of the disease. Although blood cultures remain as the best means of diagnosing bacteremia and candidemia, complementary testing with antigen tests, microbiologic investigations from other body sites, and histopathology can often aid in the diagnosis of disseminated disease, and application of emerging nucleic acid test methods and other new technology may greatly impact our ability to bacteremic and septic patients, particularly those who are immunocompromised.