Eukaryotic genomes come in a wide variety of sizes. Haploid DNA contents (C values) range > 80,000-fold without an apparent correlation with either the complexity of the organism or the number of genes. This puzzling observation, the C-value paradox, has remained a mystery for almost half a century, despite much progress in the elucidation of the structure and function of genomes. Here I argue that new approaches focussing on the genetic mechanisms that generate genome-size differences could shed much light on the evolution of genome size.