This chapter reviews older findings and highlights new findings regarding host blood-derived factors that remain immunologically active after ingestion by feeding arthropods. Bloodfeeding behavior of disease-transmitting arthropods juxtaposes vertebrate and invertebrate immune systems since blood contains not only nutrients but also an array of immune cells and molecules as well as potential pathogens and pathogen-associated molecules. Ingestion of human insulin, a hormone and growth factor with pleiotropic physiological functions, could significantly increase oocyst densities of Plasmodium falciparum, the most important human malaria parasite, in the Asian malaria vector Anopheles stephensi and in the African malaria vector Anopheles gambiae. This was demonstrated in 1994. The insulin signaling cascade, or ISC, is very highly conserved in aedine and anopheline mosquitoes. The growth factor and cytokine transforming growth factor β1 (TGF-β1) are present in circulating human blood, are pleiotropic in their effects on cell growth, anti-pathogen immunity, and inflammation, and play a critical role in regulating “immunological balance” during malaria parasite infection. Systems biology approaches have been applied in analyses of complex biological processes such as sepsis, trauma, and wound healing as well as host–pathogen interactions. Based on recent discoveries, it is likely that additional blood factors that are functional in both the mammal and in the arthropod remain to be identified. To better understand these complex interactions, a systems biology approach may be necessary to study the impact of the interacting components of vertebrate and invertebrate immunity on arthropod-borne pathogen transmission.