Bacteremia and sepsis are major health concerns. Despite intensive research, there are only a limited number of successful treatment options, and it is difficult to see the forest for the trees when considering the pathogenesis of this condition. Studies in the last decade have shown that a major pathophysiologic event in sepsis is the progression from proinflammation to an immunosuppressive state. However, recent genome-based data indicate that sepsis-related inflammatory responses are highly variable, which calls in question the classic two-phase model of sepsis. Adequate and timely antimicrobial treatment is a cornerstone for survival in patients with bacteremia and sepsis. However, microbial resistance has emerged as an increasing challenge for clinicians and with an increasing number of resistant pathogens causing infections, selection of empiric antimicrobial treatment has become difficult. Treatment options currently under way are targeted to enhance immune responses, rebalance the regulation of the dysregulated immune system, remove endotoxin and block/inhibit apoptosis.