For more than 60 years, evolutionary biologists have debated the issue of whether the processes of genetic change observable within populations (microevolution) can provide an adequate explanation for the large-scale patterns in the history of life (macroevolution). In general, population geneticists have argued in favor of microevolutionary extrapolation, whereas paleontologists have sought to establish an autonomous and hierarchical macroevolutionary theory based on the operation of selection at several levels of biological organization (especially species). The massive variation in eukaryotic genome sizes (haploid nuclear DNA contents, or “C-values”) has similarly been a subject of debate for more than half a century, and it has become clear that no one-dimensional explanation can account for it. In this article, the basic concepts of macroevolutionary theory are reviewed and then applied to the long-standing puzzle of genome size variation (the “C-value enigma”). Genome size evolution provides a clear example of hierarchy in action and therefore lends support to the theoretical approach of macroevolutionists. Perhaps more importantly, it is apparent that genome evolution cannot be understood without such a hierarchical approach, thereby providing an intriguing conceptual link between the most reductionistic and expansive subjects of evolutionary study.