The high mortality and morbidity of severe sepsis and septic shock had not been reduced during the two recent decades, despite a number of advances in the field of supportive and adjunctive sepsis therapies. The reason might be that important steps towards overcoming of sepsis - early diagnosis, the surgical resection of the infectious focus and an adequate antibiotic treatment - at present are still suboptimal and have to be improved. However, worldwide growing resistances of pathogens against the common antibiotics are detected. In opposite, no major progress in the development of new antibiotics, mainly for the treatment of Gram-negative non-fermenter infections like Pseudomonas aeruginosa, can be predicted for the next years. Therefore, sepsis treatment must be focused on prevention of infection, and on an optimised application of current antibiotic substances. The key factors are a broad, high dose, and early applicated initial treatment, a de-escalation strategy according to the clinical course supported by the application of novel molecular markers, and - with exceptions - a limitation of treatment to 7 to 10 days. A closer cooperation between microbiologists, infection control specialists and clinical infectious disease consultants may be a key factor to overcome the raising problems in the future.