The exposome describes the totality of internal and external environmental exposures, across the life course. Components of the exposome have been linked to an increased risk of various, major diseases. To identify the precise nature, and size, of risk, in this complex mixture of exposures, powerful tools are needed to link exposure, cellular consequences, and health/disease. The most biologically informative biomarkers of the exposome should, to varying extents, reflect the dose of the exposure on the body or target organ(s), a subsequent effect on the biological system and, ideally, possess a role in disease. Modification of nucleic acids (NA) is a key consequence of environmental exposures, and while cellular DNA adductomics aims to evaluate the totality to DNA modifications in the genome, an approach which encompasses modifications of all nucleic acids, would be far more comprehensive, and therefore informative. To address this, we propose a cellular and urinary NA adductomics approach for the assessment of both DNA and RNA modifications, including modified (2’-deoxy)ribonucleosides (2’dN/rN), modified nucleobases (nB), plus: DNA-DNA, RNA-RNA, DNA-RNA, DNA-protein, and RNA-protein crosslinks (DDCL, RRCL, DRCL, DPCL, and RPCL, respectively). Supporting the feasibility of this approach, we presented preliminary, proof-of-principle results, which revealed the presence of over 1,000 modified NA moieties, and at least six types of NA modifications, in a representative, pooled urine from healthy subjects, including modified 2’-dN, modified rN, modified nB, DRCL, RRCL and RPCL, many of which were novel/unexpected. We suggest that NA adductomics will provide a more comprehensive approach to the study of nucleic acid modifications, which will facilitate a range of advances, including the identification of novel, unexpected modifications e.g., RNA-RNA, and DNA-RNA crosslinks; key modifications associated with mutagenesis; agent-specific mechanisms; and adductome signatures of key environmental agents, leading to the dissection of the exposome, and its role in human health/disease, across the life course.