Drug-related adverse reactions leading to valve disease or valvulopathy were first identified in the 1960s. These were associated with patients taking anti-migraine ergot-derivative drugs, anti-anorectics, anti-Parkinson's drugs, or other anti-depressant drugs. In general, these drugs have serotonergic, dopaminergic, or β-adrenergic activity, being either agonists or reuptake inhibitors of the aforementioned neurotransmitter pathways. Recent work has focused on several possible mechanisms for valvulopathy, specifically highlighting the serotonin or 5-hydroxy-trypta-mine-2B (5-HT2B) receptor subtype and the 5-HT transporter as mediators that cause expression of myofibroblast phenotype, excessive cell proliferation, leading to valve fibrosis. Most of these studies and reviews, however, were not reported in the context of the mechanical environment of the valve, which by itself is an important factor in the initiation and progression of valve disease. It is also not known whether patients who have altered mechanical environments in their cardiovascular system, such as those who are hypertensive or have functional cardiac disease, such as ischemic ventricular dilation, or those who have an increased propensity for developing drug-induced valvulopathy. In the present review, we highlight the potential role of hemodynamics and the mechanical environment in influencing these drug-induced valvulopathies, focusing on serotonin-mediated disease and the need for further study of this topic.