Severe sepsis and septic shock are the major healthcare problem with high mortality and increasing incidence. Most cases of septic shock are caused by gram-negative bacilli or gram-positive cocci. In diagnostic algorithm, microbial culture and molecular analysis of tissue and body liquid should be obtained in patients with documented history of infection. Morphological analysis of tissue should be performed for diagnostic purpose in cases where the results of diagnostic tests are negative or when the patient clinically deteriorates despite standard therapeutic management of severe sepsis and septic shock. Morphological changes that can be found in a patient with sepsis include reversible and irreversible cell injury, cell necrosis, inflammatory and other pathological changes that can cause functional organ failure. Analysis of infectious agents can be performed using special methods, histochemical, immunohistochemical and immunofluorescence staining. Morphological analysis of pathological processes can be performed in cases of patient death. Autopsy is one of the most reliable methods to validate clinical diagnosis. In a patient with severe sepsis and septic shock, morphological analysis of tissue and organs, which can be performed during diagnostic algorithm, as well as on autopsy, presents diagnostic and final validation of clinical diagnosis and contributes to appropriate patient care, therapy and improved health quality.