Infectious diseases are caused by microorganisms that release toxins or invade body tissues. The most common pathogenic organisms are bacteria, viruses, fungi, protozoa, and helminths. Systemic infections usually cause fevers, chills, sweats, malaise, and occasionally headache, muscle and joint pain, or changes in mental status, and even septic shock-MODS. Infectious diseases have always threatened populations and caused great loss of life in history, but since the last century, with the discovery of antibiotics, historical trends have been reversed. It is reported that between 1990 and 2017, age-standardized disability-adjusted life year (DALY) rates decreased by 41.3% (38.8-43.5) for infectious diseases. However, in 2017, lower respiratory infections are still ranked as the third cause of DALYs. Drug therapy is the one of most critical management strategies for infectious diseases. Efficacy and safety of drug therapy should always be considered, especially in elders, neonates and immunosuppressed patients. Off-label drug therapy has been performed for complex infectious diseases, especially for new emerging infectious diseases. However, off-label drug therapy can be extremely complex: some are prone to rational use, while others are more susceptible to the issues of irrational use. With the increasing rate of publication of data in this area, new evidence for the efficacy and safety of different treatment approaches is constantly developing. Thus, rigorous analysis of such data is imperative, which will guide future clinical practice and guidelines.