<p>Genetic variation influences human physiology across biological scales from molecules to cells, tissues, organs and the whole organism. Unravelling how variants and their genetic effects propagate across these levels, through molecular interactions, cellular programmes and tissue architectures, to shape phenotypes remains a central challenge in human genetics. Resolving this challenge requires deciphering the genetic architecture of each biological layer and developing systems-level analyses that aim to integrate across scales. Network-based and computational approaches, including artificial intelligence, offer opportunities to move beyond statistical associations towards a context-aware, mechanistic understanding of the genetics underlying human traits and disease, although integration across layers remains limited. Here we review recent advances in mapping genetic effects across biological scales, from intracellular networks that capture molecular interactions, through single-cell and spatial omics approaches that define cellular and tissue contexts, to population-scale imaging genomics that links genetic variation to organ-level and organismal phenotypes. We discuss emerging strategies and remaining challenges for integrating these layers into mechanistic models of genotype–phenotype relationships.</p>