Coronaviruses and the diseases associated with them were once only of significant veterinary interest and very little importance to public health. This changed in 2003, when the cause of an outbreak of a severe form of pneumonia was isolated as the severe acute respiratory syndrome (SARS) coronavirus. Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. The spike protein (S) found on the viral surface, is used for entry and is a primary determinant of cell tropism and pathogenesis. The S protein is responsible for binding to the receptor on the host cell and mediating the fusion of host and viral membranes. Fusion of the viral membrane with host cell membrane is required for the delivery of the nucleocapsid to the target cell. Membrane fusion is driven by major conformational changes within the S protein and can be triggered solely or in combination by receptor binding, low pH, or proteolysis.