The phenomenon of genome gigantism, defined as an organism’s haploid nuclear DNA content (C-value) exceeding 10 gigabases (Gb), has been demonstrated to exhibit a substantial degree of variability in mutational and selective processes across diverse lineages. Recent studies of the genome and epigenome have highlighted the interplay between the proliferation of transposable elements, DNA loss dynamics, and coevolutionary host-silencing mechanisms in shaping and maintaining these massive genomes. In this review, we synthesize emerging insights into how mutation, drift, and selection collectively determine genomic scale and explore the ecological and evolutionary contexts that facilitate or impede the phenomenon of genome gigantism.