Over the past decade, a core ambition in cancer research has been the development of ‘simple’ blood tests able to screen, diagnose or monitor cancer and to help design personalised therapies, without the need for invasive tumour biopsies. Ongoing biomarker development efforts indicate that multiple markers, used individually or as part of a multi-modal panel, are required to enhance sensitivity and specificity for early-stage cancer detection. The discovery of molecular alterations reflected in blood at multiple dimensions (genome, epigenome, transcriptome, proteome, metabolome) and integration of the resultant multi-omics data has the potential to uncover novel biomarkers and to further elucidate underlying molecular pathways. Here, we review recent advances in multi-omics liquid biopsy approaches and introduce the ‘Nano-omics’ approach: the development and utilisation of nanotechnology tools for the enrichment and subsequent ‘omics’ analysis of the blood-circulating cancer biome.