The metabolic syndrome (MetS), first introduced by Haller in 1975, was sometimes also known as insulin resistance syndrome, syndrome X, and plurimetabolic syndrome. In 1989, it was rechristened by Kaplan as the “Deadly Quartet” based on a consolidation of central obesity, impaired glucose tolerance, dyslipidemia, and systemic hypertension. MetS is positively associated with a pro-inflammatory and pro-thrombotic state, attributed to increased pro-thrombotic and inflammatory marker activity. Moreover, MetS is frequently associated with increased atherosclerotic cardiovascular disease, impaired glucose tolerance, hyperuricemia, obstructive sleep apnea, and chronic kidney disease. Despite concerted endeavors worldwide, the complexity of the pathophysiology of metabolic syndrome still needs to be clearly understood. Currently, therapeutic possibilities are confined to individual therapy for hyperglycemia, hypertension, hypertriglyceridemia, hyperuricemia, regular physical exercise, and a restricted diet. In this review, progress regarding the understanding and pathophysiology of MetS; recent emerging technologies, such as metabolomics and proteomics; the relation of MetS with obesity, diabetes, and cardiovascular diseases; and the association of MetS with COVID-19 are discussed.