This study presents a new technique for the orthotopic engraftment of human lung tumours in SCID mice and demonstrates the importance of a more clinically relevant route of tumour propagation for the study of metastatic potential. The orthotopic engraftment of human lung tumour biopsy specimens was performed via an anterior thoracotomy into SCID mice. Engraftment of non-small cell lung cancer specimens from nine patients into 52 SCID mice yielded a 31% engraftment rate and a 50% metastasis rate. Unlike subcutaneous inoculation, the engraftment rates following the orthotopic inoculation did not vary between squamous cell carcinomas and adenocarcinomas. Direct visceral pleural invasion was seen in most cases. Orthotopically placed tumours grew 5-fold by 4 to 6 months. Unique to this model was the observation of metastasis to clinically relevant sites, such as the adrenal gland and supraclavicular lymph nodes. Contralateral lung metastases were also noted in 37.5%, and one ovarian metastasis occurred. The procedure was well tolerated, with survival rates of 98%.