Pulmonary toxicity has frequently been recognized as a potentially serious complication associated with sirolimus therapy. It consists of a wide spectrum of syndromes most characterized by the presence of lymphocytic alveolitis and lymphocytic interstitial pneumonitis. The most commonly presenting symptoms are fever and dyspnea. Chest computed tomography generally reveals bilateral, patchy, or diffuse alveolointerstitial infiltrates. The discontinuation or dose reduction of sirolimus usually leads in most cases to a good outcome with complete clinical and radiologic resolution. However, to establish a diagnosis is difficult because of the absence of specific diagnostic criteria, and in rare cases, it could be fatal or life threatening when the diagnosis was delayed. Here, we reported 2 severe cases of acute respiratory distress attributed to the therapy of sirolimus in solid organ transplant recipients. Although the diagnostic course was difficult, withdrawal of sirolimus and temporary administration of steroids eventually resulted in a rapid recovery in both 2 patients. In addition, possible mechanisms, clinical characteristics, approach to diagnosis, and treatment strategies of sirolimus-induced pulmonary toxicity were also discussed in this article.