Development of robust, in vivo like tissues in vitro holds the potential to create regenerative medicine-based therapeutics, provide more physiologically significant preclinical models and supply a pharmacological and toxicological screening platform that reflects in vivo systems in both complexity and function. This protocol describes a simple, robust, multilayer replica molding technique in which poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) diacrylate (PEGDA) are serially replica molded to develop microfluidic PEGDA hydrogel networks embedded within independently fabricated PDMS housings, using a combination of soft and photo-lithography. This work has direct applications toward the development of robust, complex, cell-laden hydrogels for in vitro diagnostics and regenerative medicine applications.