The pharmaceutical development of a cardiovascular polypill presents several unique challenges. The selection of the type and number of active drugs to be incorporated requires important consideration of clinical, pharmaceutical and commercial issues, and the final decision with regard to the polypill's components depends on how these issues are prioritized. Once the drug combination has been chosen, developers must determine which pharmaceutical formulation should be used. The most appropriate method of drug delivery can vary markedly and depends on the characteristics of the drugs to be combined. Finally, careful consideration of how to gather the type of information required by regulatory agencies before a particular polypill can be approved for use in the general population is crucial. Although the association of multiple, active ingredients in a single dosage form would represent a major step forward in the prevention of cardiovascular conditions, a careful evaluation of all the above-mentioned variables and a well thought-out development plan is mandatory to maximize the chances of success.