An overview of gram-negative sepsis is presented, and the need for improved treatment for this condition is emphasized. The availability of new and more potent antimicrobial agents has not substantially altered the mortality from sepsis and septic shock. Gram-negative infection, bacteremia, sepsis, and septic shock remain major clinical problems, particularly among hospitalized patients. The estimated incidence of gram-negative sepsis in the United States alone is 200,000 cases annually. The predominant pathogens are Escherichia coli, Klebsiella, and Pseudomonas aeruginosa. Mortality is strongly influenced by the host's clinical status and age and the development of shock; it may reach 90% in patients with rapidly fatal disease. Analysis of risk factors and use of criteria for categorizing severity of disease can be helpful in designing new treatments, identifying potential recipients of such agents, and evaluating outcome of therapy. Because bacterial endotoxin plays a pivotal role in triggering the biological cascade of mediators in the septic process, a new therapy has been developed, immunotherapy with monoclonal antibodies that neutralize lipopolysaccharide by binding to lipid A. Successful treatment of gram-negative sepsis requires appropriate patient identification and timely intervention. While antimicrobial agents remain important, monoclonal antibodies hold promise as a new therapeutic intervention.