Introduction Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods A total of 26 sites in England, Wales and Scotland, recruiting samples from 7,814 patients for genetic examination between 2011-2013. Tumor types involved were breast, colorectal, lung, prostate, ovary cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by National Cancer Research Institute Clinical Study groups. Results 10,754 patients (98% of those approached) consented to participate, from which 7,814 tumor samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 lung cancer patients, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumor heterogeneity of colorectal cancer (1550 patients) was observed , including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low and high grade serous ovarian cancers. Conclusion Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx.