Myxovirus resistance (MX) proteins are pivotal players in the innate immune response to viral infections. Less than 10 years ago, three independent groups simultaneously showed that human MX2 is an interferon (IFN)-stimulated gene (ISG) with potent anti-human immunodeficiency virus 1 (HIV-1) activity. Thenceforth, multiple research works have been published highlighting the ability of MX2 to inhibit RNA and DNA viruses. These growing bodies of evidence have identified some of the key determinants regulating its antiviral activity. Therefore, the importance of the protein amino-terminal domain, the oligomerization state, or the ability to interact with viral components is now well recognized. Nonetheless, there are still several unknown aspects of MX2 antiviral activity asking for further research, such as the role of cellular localization or the effect of post-translational modifications. This work aims to provide a comprehensive review of our current knowledge on the molecular determinants governing the antiviral activity of this versatile ISG, using human MX2 and HIV-1 inhibition as a reference, but drawing parallelisms and noting divergent mechanisms with other proteins and viruses when necessary.