A significative proportion of patients with pulmonary-related COVID-19 initially present with « silent » or « happy » hypoxemia, a term denoting an absence of dyspnea or other respiratory distress symptoms in face of profound hypoxemia. COVID-19 is a multisystemic disease characterized by the diffusion of SARS-COV-2 through the blood and a widespread secondary immune response. Most of the organs are involved, including the brain and this translates into the development of acute encephalopathy and other complications. Silent hypoxemia and the consequent "vanishing dyspnea" represent a loss of warning signal and may be associated with a rapid clinical worsening and a fatal outcome. In this article, we will describe the physiological basis of ventilation and we will elucidate the different pathophysiological mechanisms underlying the phenomenon of silent hypoxemia in COVID-19.