Because pigs are susceptible to both avian and human influenza viruses, genetic reassortment between avian, human, and/or swine influenza viruses in the pig host can lead to the generation of novel influenza A viruses (Ma et al. 2009). Since the first serological evidence of a swine influenza virus (SIV) infecting humans in 1958, sporadic cases have continued to occur. In recent years, case reports have been increasing, seemingly in concert with modern pig farming and the emergence of triple reassortant SIVs in swine. SIV infections in man generally are mild or subclinical, and often are not diagnosed; however, SIV infections can be quite serious in patients with underlying medical conditions. As of August 2010, 73 case reports of symptomatic human SIV infections have been documented in the medical literature or reported by health officials (excluding cases of the 2009 pandemic H1N1 influenza virus), of which 7 infections (10 %) resulted in death. While exposure to swine is often considered a risk factor for human SIV infections, 37 of 73 (51 %) reported cases had no known exposure to pigs; consequently, SIV may be crossing the species barrier via transmission routes yet to be acknowledged. In addition, human-to-human transmission was suspected in 10 of 34 (30 %) of the cases with epidemiological investigation. This chapter discusses the observations of illness and infections in humans, risk factors associated with infection, and methods for diagnosing human infections of SIV.