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Circulating tumour DNA (ctDNA) detection of molecular residual disease (MRD) in solid tumours correlates strongly with patient outcomes and is being adopted as a new clinical standard. ctDNA levels are known to correlate with tumor volume, and although the absolute levels vary across indication and histology, its analysis is driving the adoption of MRD. MRD assays must detect tumor when imaging cannot and, as such, require very high sensitivity to detect the low levels of ctDNA found after curative intent therapy. The minimum threshold is 0.01% Tumour Fraction but current methods like Archer and Signatera are limited by detection sensitivity resulting in some patients receiving a false negative call thereby missing out on earlier therapeutic intervention. Multiple vendors are increasing the number of somatic variants tracked in tumour-informed and personalized NGS assays, from tens to thousands of variants. Most recently, assays using other biological features of ctDNA, e.g methylation or fragmentome, have been developed at the LOD required for clinical utility. These uniformed, or tumour-naive and non-personalised assays may be more easily, and therefore more rapidly, adopted in the clinic. However, this rapid development in MRD assay technology results in significant challenges in benchmarking these new technologies for use in clinical trials. This is further complicated by the fact that previous reference materials have focused on somatic variants, and do not retain all of the epigenomic features assessed by newer technologies. In this Comments and Controversy paper, we detail what is known and what remains to be determined for optimal reference materials of MRD methods and provide opinions generated during three-years of MRD technology benchmarking in AstraZeneca Translational Medicine to help guide the community conversation.