Coronaviruses (CoV) are large enveloped RNA viruses of animals and humans associated mostly with enteric and respiratory diseases. These viruses were earlier considered more of a veterinary interest and were associated to humans with mild flu. The last decade brought outbreaks with high mortality rates caused by CoV transmission from animals to man. This remarkable cross-species transmission potential is related to CoV adaptation to a variety of cell surface molecules for entry into host cells. The CoV particles bear exposed spike (S)proteins in their envelope that attach to specific cell entry receptors, which determines CoV host cell range and tropism. CoV can recognize diverse entry receptors, but they preferentially use membrane bound ectoenzymes. A subset of CoV recognizes the cell surface aminopeptidase N (APN), a membrane-bound metalloprotease. APN (CD13) is a moonlighting ectoenzyme linked to multiple functions such asangiogenesis, cell adhesion and tumorogenesis. It cleaves neutral amino acid side chains fromthe N-terminus of oligopeptides. It is distributed in wide variety of tissues and its expressionis dysregulated in tumors.