The initial assessment of patients with infectious diseases is challenging because of the extremely broad differential diagnosis as well as different host pathogen interactions influenced by a different immune status. The formal initial assessment, including the present and past medical history, thorough physical examination, clinical first impressions as well as routine laboratory analyses, is the basis of every preliminary diagnosis. Specific chief complaints have to be recognized in order to narrow down the differential diagnosis. In cases of life-threatening illnesses, such as septicemia, endocarditis, bacterial meningitis and severe pneumonia, the first diagnostic and therapeutic steps should be performed in a rapid sequence: bacterial blood samples, sputum and/or liquor samples are required and the initial antibiotic therapy has to be chosen empirically as the relevant bacterial spectrum related to the suspected illness must be covered. In less urgent cases it is recommended that a multi-step diagnostic approach be carried out which takes the differential diagnosis into account and prioritizes the probabilities. In the latter situation antibiotic treatment should be delayed to diagnose the infection correctly. Importantly, atypical courses must necessitate careful and critical reassessment of the diagnosis.