Inadequate antibiotic therapy, generally defined as microbiologically ineffective anti-infective therapy against the causative pathogen, can influence patient outcome. However, the detrimental effects of inadequate antibiotic therapy seem to become weaker in the most severely ill patients with short life expectancies. In addition to severity of illness, other methodological issues should be carefully examined in studies assessing the excess mortality due to inadequate therapy. To adjust for confounding as much as possible in order to obtain an unbiased estimate of the magnitude of the effect of inadequate therapy is a key methodological challenge for future research. With regard to the choice of antibiotic agents, beta-lactam and aminoglycoside combination therapy does not seem to improve clinical outcome in most cases of sepsis caused by gram-negative bacteria, including Pseudomonas aeruginosa bacteremia. A potential benefit of combination therapy in the treatment of severe pneumococcal sepsis has been suggested in several observational studies, but recently published data have disputed this hypothesis. Finally, better risk scores and laboratory tools are urgently needed to improve the adequacy of empirical antibiotic therapy and patient outcomes.