The use of oral insecticidal molecules (small molecules, peptides, dsRNA) via spray or plant mediated applications represents an efficient way to manage damaging insect species. With the exception of Bt toxins that target the midgut epithelium itself, most of these compounds have targets that lie within the hemocoel (body) of the insect. Because of this, one of the greatest factors in determining the effectiveness of an oral insecticidal compound is its ability to traverse the gut epithelium and enter the hemolymph. However, for many types of insecticidal compounds, neither the pathway taken across the gut nor the specific genes which influence uptake are fully characterized. Here, we review how different types of insecticidal compounds enter or cross the midgut epithelium through passive (diffusion) or active (transporter based, endocytosis) routes. A deeper understanding of how insecticidal molecules cross the gut will help to best utilize current insecticides and also provide for more rational design of future ones.