The standard treatment for obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP). Depending on selection criteria and quality of care, up to 50% of patients with OSA do not tolerate CPAP. For patients who cannot tolerate CPAP despite good quality care, pharmacological treatment would be a desirable alternative. The mechanisms by which pharmacological treatment is supposed to improve OSA include, amongst others, an augmentation in pharyngeal dilator muscle tone, an increase in ventilatory drive, a reduction in airway resistance and alterations in pharyngeal surface tension forces. In humans, most recent pharmacological approaches to the treatment of OSA in clinical trials have focused on modulating serotoninergic and cholinergic activities, as both have been shown to augment pharyngeal dilator muscle tone. However, currently there is not enough evidence to recommend any particular drug treatment for OSA. Methodological issues of published clinical trials on pharmacological OSA treatment make it difficult to draw definitive conclusions and inform further drug developments in this area. In this article, the pitfalls of clinical trials on pharmacological OSA therapy are summarised and potential solutions and directions for future studies are given.