Isoprene is a key building block for biological polymers across all domains of life. Isoprene is a gas with signaling roles in plants, but isoprene polymers have many bioactive forms with diverse functions across biology. Prenyl polymers are used to prenylate specific proteins on biological membranes, and are precursors to sterols and steroids, are integrated into other membrane associated co-factors such as quinones, and facilitate protein glycosylation. Polyprenes come in multiple sizes, synthesized by the appropriate prenyltransferase enzyme. Rubber is a very long natural polyprene with wide industrial application, while other isoprene polymers may only be 10-15 carbons. Polyprenes generated by prenyltransferases can be either cis-or trans-with respect to a 1,4 alkene bond. Despite the disparate size of the end products, the cisprenyltransferase enzymes found across biology share structural features. Prokaryotic cis-prenyltransferases (cisPTs) are well characterized in structure and function, and tend to generate shorter isoprenoid products that fit into the hydrophobic pocket near the enzyme active site, creating a clear mechanism to regulate product size. By contrast, eukaryotic cisPTs generate much longer polyprenes that cannot fit into the active site and hydrophobic pocket within the protein. The heterotetrameric human cis-prenyltransferase (h-cisPT), which synthesizes the precursor for dolichol, is composed of two identical heterodimers (Fig. ). One subunit, dehydrodolichyl diphosphate synthase (DHDDS), contains the catalytic site for prenyl chain extension. The catalytic site contains an active site 1 (S1), which contains the growing prenyl chain, while S2 binds isopentenyl diphosphate (IPP), a five carbon building block which is iteratively added to the prenyl chain. Past research shows that h-cisPT membrane association is strongly linked to prenyl substrate extension, and DHDDS may be able to independently associate to the membrane. The other subunit, Nogo-B receptor (NgBR), lacks catalytic residues and is thought to anchor the complex to the ER membrane and contribute to the active site architecture or potentially other interaction partners. Long prenyl chains are released from h-cisPT when they reach a length of 17-20 isoprene units, or around 100 carbons. Such a long prenyl chain would be highly hydrophobic, and very unlikely to dissociate from h-cisPT in solution. This implies that h-cisPT must associate to the membrane for product release and may be frequently associated to the membrane. Through molecular simulation and molecular biology techniques, we determine the binding pose for the soluble domains of h-cisPT to ER membranes during synthesis and investigate potential downstream impacts on product release.