Cell size is highly variable; cells from various tissues differ in volume over orders of magnitudes, from tiny lymphocytes to giant neurons, and cells of a given type change size during the cell cycle. Larger cells need to produce and maintain higher amounts of RNA and protein to sustain biomass and function, although the genome content often remains constant. Available data indicate that the transcriptional and translational outputs scale with cell size at a genome-wide level, but how such remarkably coordinated regulation is achieved remains largely mysterious. With global and systems-level approaches becoming more widespread and quantitative, it is worth revisiting this fascinating problem. Here, we outline current knowledge of the fundamental relations between genome regulation and cell size, and highlight the biological implications and potential mechanisms of the global tuning of gene expression to cellular volume.