Salmonella Typhi continues to be a serious global health concern, resulting in more than 200,000 annual deaths. A distinguishing feature of S. Typhi is that it only infects humans, causing a life-threatening systemic infection known as "typhoid fever". This is in sharp contrast to most other Salmonellae, which can infect a variety of hosts and are usually associated with self-limiting gastroenteritis (i. e. “food poisoning”). The molecular bases for Salmonella Typhi's unique pathogenesis and host specificity will be discussed.