Studies on natural variation and network biology inherently work to summarize vast amounts of information and data. The combination of these two areas of study while creating datasets of immense complexity is critical to their mutual progress. Networks are necessary as a way to work to reduce the dimensionality inherent in natural variation with 100 s to 1000 s of genotypes. Correspondingly natural variation is essential for testing how networks may or may not be shared across individuals or species. Advances in this area of cross-fertilization including using networks directly as phenotypes and the use of networks to help in prioritizing candidate gene validation efforts. Interesting new observations on frequent presence-absence variation in gene content and adaptation is beginning to highlight the potential for natural variation in network presence-absence. This review attempts to delve into these new insights.