SARS-CoV-2 is highly transmissible and pathogenic, with nearly 6.5 million infected people dying worldwide. A severe acute respiratory syndrome is one of the primary COVID-19 outcomes, often related to bacterial co-infections. In addition, infective variants of SARS-CoV-2 have constantly emerged in different countries, causing recurrent waves of infection. These variants increase the chances of vaccine failure, even in countries with accelerated vaccination programs, such as Israel and the USA. In this brief review, the subjects addressed include aspects of the SARS-CoV-2 variants, vaccines, drug therapy, and new alternative therapies. Finally, this review also discussed articles that addressed the repositioning of drugs against the SarsCov2 MPro enzyme using in silico approaches. In addition, we discussed the repositioning of drugs in silico, which can be a valuable strategy to guide and optimize the selection of elective compounds already approved for human use. Bearing in mind that few drugs, such as nirmatrelvir, ritonavir (Paxlovid), molnupiravir, and some monoclonal antibodies, have received authorization throughout the COVID-19 pandemic, according to Food and Drug Administration guidelines.