The study of genome size (GS) and its variation is so fascinating to the scientific community because it constitutes the link between the present-day analytical and molecular studies of the genome and the old trunk of the holistic and synthetic view of the genome. The GS of several taxa vary over a broad range and do not correlate with the complexity of the organisms (the C-value paradox). However, the biology of transposable elements has let us reach a satisfactory view of the molecular mechanisms that give rise to GS variation and novelties, providing a less perplexing view of the significance of the GS (C-enigma). The knowledge of the composition and structure of a genome is a pre-requisite for trying to understand the evolution of the main genome signature: its size. The radiation of mammals provides an approximately 180-million-year test case for theories of how GS evolves. It has been found from data-mining GS databases that GS is a useful cyto-taxonomical instrument at the level of orders/superorders, providing genomic signatures characterizing Monotremata, Marsupialia, Afrotheria, Xenarthra, Laurasiatheria, and Euarchontoglires. A hypothetical ancestral mammalian-like GS of 2.9–3.7 pg has been suggested. This value appears compatible with the average values calculated for the high systematic levels of the extant Monotremata (∼2.97 pg) and Marsupialia (∼4.07 pg), suggesting invasion of mobile DNA elements concurrently with the separation of the older clades of Afrotheria (∼5.5 pg) and Xenarthra (∼4.5 pg) with larger GS, leaving the Euarchontoglires (∼3.4 pg) and Laurasiatheria (∼2.8 pg) genomes with fewer transposable elements. However, the paucity of GS data (546 mammalian species sized from 5,488 living species) for species, genera, and families calls for caution. Considering that mammalian species may be vanished even before they are known, GS data are sorely needed to phenotype the effects brought about by their variation and to validate any hypotheses on GS evolution in mammals.