Typhoid fever, caused by Salmonella enterica seroptype Typhi (S typhi), has an estimated worldwide prevalence of 12–33 million cases. The pathogenesis of this disease depends on the ingested inoculum size of S typhi, the virulence of the strain, the host’s immune response and previous exposure, and local protective factors. Numerous extra-intestinal complications can occur with S typhi infection, including the involvement of the central nervous system (3–35%), cardiovascular system (1–5%), pulmonary system (1–86%), bone and joints (≤1%), hepatobiliary system (1–26%), genitourinary system (<1%), and others. Due to an increase in multidrug-resistant S typhi, fluoroquinolones and third-generation cephalosporins have been increasingly used for typhoid fever and its complications. We describe the epidemiology, clinical manifestations, pathogenesis, and treatment of extra-intestinal S typhi infections.