The field of complex trait-gene interaction research has expanded exponentially in recent years, and new insights into the ways patients respond to surgical stimuli have arisen from this body of work. From a physiological systems perspective, thoracic surgical procedures (thoracotomy in particular) represent a massive input stimulus, and it is, therefore, not surprising that approximately 30% of these patients experience an adverse postoperative event. The best risk prediction models have typically explained about 60% to 70% of the risk, leaving a large residual component unaccounted for. It is quite possible that there is a genetic (heritable) component to this residual risk. This article explores some of the concepts underlying gene-disease interactions, the preliminary work that has been done to date in this area, and finally discusses some of the more important methodological issues involved in complex trait association study design.