Recent genetic analyses of paired samples from primary tumours and disseminated tumour cells have uncovered a bewildering genetic disparity. It was therefore proposed that ectopically residing tumour cells disseminate early and develop independently into metastases parallel to the primary tumour. Alternatively, these cells may represent an irrelevant cell population unable to spawn metastases whereas only cells that disseminated late in primary tumour development (which therefore are similar to the primary tumour) will form manifest metastasis. Here, we review comparative analyses of paired samples from primary tumours and disseminated tumour cells or primary tumours and metastases. The data demonstrate a striking disparity, questioning the use of primary tumours as surrogate for the genetics of systemic cancer. In the era of molecular therapies that build upon genetic defects of tumour cells, these data call for a direct diagnostic pathology of systemic cancer.