The pharmacokinetics of different barbiturates have been studied extensively and the relationship of their duration of action to their clinical use has been known for decades. While these particular compounds have largely been displaced by agents with better therapeutic indices, barbiturate use remains relatively common and important in both inpatient and outpatient settings. Their mechanism of action is to bind to inhibitory GABAA receptors in the CNS causing and potentiating the opening of neuronal chloride ion channels thus having a sedative and CNS depressant effect. All psychotropic barbiturates feature di-substitution at the C5 position of the barbituric acid prototype. This is also the primary factor by which physiologically active barbiturates differ from one another and a major mediator of lipophilicity and duration of action. However, in this review, inconsistencies in certain commonly held notions about the structure-activity relationship of barbiturates were found. Commonly accepted chemistry for the structure-activity relationship of barbiturates holds that substitution of larger alkyl groups, alicyclic, and aromatic groups, as well as branching and unsaturation, lead in general to more lipophilic compounds with a shorter biological half-life. This rationale may have limitations in the case of barbiturates as proposed in this review. There is poor correlation between nine clinically used barbiturates' octanol:water partition coefficients (log(P) values) and their respective half-lives. However, a strong correlation between pKa values and half-life was found. The current clinical relevance of these findings is discussed as well as their pertinence to future design and use of barbiturates.