Background <p>Mosquitoes transmit a diverse range of deadly pathogens, including dengue and <i>Plasmodium</i> spp., when they consume the blood of vertebrate hosts in order to nutritionally provision their eggs. However, mosquito species from multiple genera have independently evolved the ability to produce eggs without blood. The molecular and physiological processes underlying the evolution of blood-independent reproduction are largely unresolved, in part because the two most well-studied models of mosquito reproductive physiology and genetics are obligate blood feeders. Herein, we integrate life-history, genomics, and gene expression to identify physiological processes and candidate genes associated with the evolution of blood-independent reproduction in a non-model vector mosquito, <i>Aedes albopictus</i>.</p> Results <p>Relative to a blood-dependent (control) population, females selected for blood-independent reproduction exhibit a longer larval development period and larger adult size, implying increased nutrient sequestration at the larval stage. Additionally, blood-independent larvae exhibit higher expression of amino acid and lipid storage genes (<i>hex1.1</i> and <i>lsd-2</i>) relative to blood-dependent larvae. Linkage clusters and F_ST outliers identify a ca.&#xa0;40&#xa0;Mb genomic region that is highly differentiated between blood-independent and blood-dependent lines. Moreover, microRNAs and mRNAs related to reproductive physiology are differentially abundant between adults of the selected vs. control lines.</p> Conclusions <p>Multiple lines of evidence indicate that larval nutrient sequestration and altered regulation of vitellogenesis have contributed to the rapid evolution of blood-independent reproduction in <i>Ae. albopictus</i>. Overlapping evidence also identifies proposed candidate genes affecting these processes. These results provide a foundation for developing novel paradigms to suppress disease transmission by vector mosquitoes.</p>