Demographic and clinical risk factors may only partially predict short- and long-term outcomes after thoracic transplantation. The interindividual variability seen in rejection profiles could be related to the recipient's or donor's genetic background. Rejection, either acute or chronic, elicits an alloimmune response that involves a complex network of cytokines, growth factors, adhesion molecules, and other molecules, which may modulate the immune response toward rejection or, conversely, mediate graft acceptance. Herein, the authors discuss the current evidence regarding the importance of genetic polymorphisms as independent predictors of allograft outcome. They believe that pretransplant genotype profiling of patients, in combination with other relevant clinical information, might be useful to predict the risk for posttransplant adverse events and also to facilitate the implementation of individualized immunosuppression.