The long use of ephedrine, amphetamines, cocaine, LSD and more recently 3,4-methylenedioxy-N-methylamphetamine (MDMA; “Ecstasy”) allows us to predict with some confidence what cardiovascular risks are likely to be associated with novel psychoactive substances (NPS). Once the probably multiple biological activities of a compound are known it is possible to define the likely risks of cardiovascular toxicity. Agonists of 5-HT2A receptors or alpha-adrenoceptors may cause vasoconstriction and tissue ischemia. Drugs which have agonist affinity for 5-HT2B receptors will probably promote heart valve fibrosis leading to heart failure. Compounds that interfere with uptake of dopamine or 5-hydroxytryptamine (5-HT) are likely to also have effects on noradrenergic neurotransmission and lead to sympathomimetic effects on the heart and vasculature. Drugs that cause dopamine release, or inhibit uptake are likely to be addictive and lead to chronic use. Other drugs (particularly the so-called empathogens) are associated with weekly usage in social settings; over time such use can lead to cardiovascular harm. Defining which of these effects NPS have is an important element of predicting the harm they may cause and informing those appointed to introduce regulations to control them.