Cardiovascular disease remains the leading cause of death worldwide, yet despite massive investment in drug discovery, the progress of cardiovascular drugs from lab to clinic remains slow. It is a complex, costly pathway from drug discovery to the clinic and failure becomes more expensive as a drug progresses along this pathway. The focus has begun to shift to optimisation of in vitro culture methodologies, not only because these must be undertaken are earlier on in the drug discovery pathway, but also because the principles of the 3Rs have become embedded in national and international legislation and regulation. Numerous studies have shown myocyte cell behaviour to be much more physiologically relevant in 3D culture compared to 2D culture, highlighting the advantages of using 3D-based models, whether microfluidic or otherwise, for preclinical drug screening. This review aims to provide an overview of the challenges in cardiovascular drug discovery, the limitations of traditional routes, and the successes in the field of preclinical models for cardiovascular drug discovery. It focuses on the particular role biomimicry can play, but also the challenges around implementation within commercial drug discovery.