The biological plausibility, available preclinical evidence, and feasibility of bronchoscopic delivery make ATII cell transplantation an intriguing therapeutic modality. However, a major challenge to future clinical investigation, in addition to designing a trial with a reasonable placebo arm that demonstrates efficacy, will be establishing and monitoring cell engraftment. In other examples of heterologous cell transplantation, both innate and adaptive immune responses have limited the potential success despite the use of immunosuppressive therapy comparable to that used for solid organ transplantation. The posttransplantation development of human leukocyte antibodies, which was seen in 5 of 16 patients in this study, has been implicated in the failure of islet cell and hepatocyte transplantation., Development of alloimmunity may also have implications on future lung transplantation. Proof of ATII cell graft survival is essential to justify continuing potentially toxic immunosuppressive therapy and would be useful for determining the need for retransplantation. Given the absence of readily measurable biomarkers of engraftment—for example, reductions in bilirubin levels in hepatocyte transplantation—development and validation of novel surrogate measures would be instrumental. Scientific and clinical studies examining the functionality of transplanted ATII cells in surfactant production, paracrine modulation, and epithelial regeneration would also add validity. It is incumbent on the IPF community to perform thorough mechanistic and preclinical investigations, coupled with careful trial design, deserving of the personal investment of the patients who participate in these forms of clinical trials.