Several important gender differences in susceptibility, clinical manifestation and response to treatments for a number of diseases are known since a long time, although they continue to be underestimated by a multiplicity of operators, especially men. The recent COVID-19 pandemic has provided a further evidence of the importance of gender medicine. The epidemiological analysis of COVID-19 data has highlighted the presence of multiple and important gender differences, with more unfavourable scenarios for the male gender. The mechanisms underlying these gender differences are varied (including socio-behavioral, immune and viral factors) and not yet fully clarified. A gender-based approach to clinical practice also in the context of this pandemic seems to be mandatory, as it could significantly contribute to health promotion by improving the effectiveness of diagnostic and/or therapeutic approaches and, therefore, leading to important benefits primarily for the patients but also for the sustainability of the National Health System.