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Fatemeh Pourrajab,1,2 Mohamad Reza Zare-Khormizi,3 Mohammad Hasan Sheikhha4 1Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2Department of Biochemistry and Molecular Biology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 3School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 4Biotechnology Research Center, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, IranCorrespondence: Fatemeh PourrajabNutrition and Food Security Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, IranEmail mina_poorrajab@yahoo.comMohammad Hasan SheikhhaBiotechnology Research Center, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, IranTel +983538247085Fax +983538247087Email sheikhha@yahoo.comAbstract: Over the past years, several zoonotic viruses have crossed the species barrier into humans and have been causing outbreaks of severe, and often fatal, respiratory illness. The 21st century has seen the worldwide spread of three recognized coronaviruses (CoVs) which can cause pneumonia and severe acute respiratory symptoms (SARSs), SARS, MERS, and recently SARS-CoV-2. Herein, it is raising concerns about the dissemination of another new and highly lethal pandemic outbreak. Preparing for a pandemic outbreak involves a great deal of awareness necessary to stop initial outbreaks, through recognizing the molecular mechanisms underlying virus transmission and pathogenicity. CoV spike protein S is the key determinant of host tropism and viral pathogenicity which can undergo variations and makes the CoV a highly pathogenic and diffusible virus capable of sustained human-to-human transmission and spread easily. The three mentioned CoVs exhibit some similarities in S protein whereby constitute a promising target for the development of prophylactics and therapeutics in the future.Keywords: coronavirus, transmission, receptor binding, spike protein