Recent reports of mild to severe influenza-like illness in humans caused by a novel swine-origin 2009 A(H1N1) influenza virus underscore the need to better understand the pathogenesis and transmission of these viruses in mammals. Here, selected 2009 A(H1N1) isolates were assessed for their ability to cause disease in mice and ferrets, and compared with a contemporary seasonal H1N1 virus for their ability to transmit by respiratory droplets to na?ve ferrets. In contrast to seasonal influenza H1N1 virus, 2009 A(H1N1) viruses caused increased morbidity, replicated to higher titers in lung tissue, and were recovered from the intestinal tract of intranasally inoculated ferrets. The 2009 A(H1N1) viruses exhibited less efficient respiratory droplet transmission in ferrets in comparison to the high-transmissible phenotype of a seasonal H1N1 virus. Transmission of the 2009 A(H1N1) viruses was further corroborated by characterizing the binding specificity of the viral hemagglutinin to the sialylated glycan receptors (in the human host) using dose-dependent direct receptor binding and human lung tissue binding assays.