Metabolic syndrome (MetS) is a well-defined yet difficult-to-manage disease entity. Both the precipitous rise in its incidence due to contemporary lifestyles and the growing heterogeneity among affected populations present unprecedented challenges. Moreover, the predisposed risk for developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in populations with MetS, and the viral impacts on host metabolic parameters, underscores the need to investigate this mechanism thoroughly. Recent investigations of metabolomics and proteomics have revealed not only differentially expressed substances in MetS, but also the consequences of diet consumption and physical activity on energy metabolism. These variations in metabolites, as well as protein products, also influence a wide spectrum of host characteristics, from cellular behavior to phenotype. Research on the dysregulation of gut microbiota and the resultant inflammatory status has also contributed to our understanding of the underlying pathogenic mechanisms. As for state-of-the-art therapies, advancing depictions of the bio-molecular landscape of MetS have emerged and now play a key role in individualized precision medicine. Fecal microbiota transplantation, aiming to restore the host's homeostasis, and targeting of the bile acid signaling pathway are two approaches to combatting MetS. Comprehensive molecular inquiries about MetS by omics measures are mandatory to facilitate the development of novel therapeutic modalities.