Hydrogen sulfide (H2S) is an important gasotransmitter with multiple roles and is involved in several pathophysiological processes, including atherosclerosis and associated cardiometabolic comorbidities. This chapter examines the molecular mechanisms by which H2S can influence the development and progression of atherosclerosis, including its effects on vascular tone, angiogenesis, oxidative stress, and inflammation, which can also affect atherosclerotic plaque stability. Moreover, we describe how H2S affects the outcomes of cardiometabolic comorbidities associated with atherosclerosis, such as diabetes, hypertension, cardiac ischemia-reperfusion injury (IRI), stroke, metabolic-associated fatty liver disease (MAFLD), and kidney disease. Finally, we discuss how H2S levels could potentially serve as biomarkers and the potential of increasing H2S levels (both donors and metabolic pathway modulators) as promising therapeutic agents for improving vascular function, reducing plaque formation, and mitigating cardiovascular disease risk.