Materials and methods involving conditional retention domains (CRDs) are disclosed. A conditional retention domain is any domain which is retained in the ER or other secretory compartment in the absence of ligand and is released from the secretory machinery when ligand is bound, i.e. in the presence of ligand. Also disclosed are fusion proteins containing CRDs and cells expressing such fusion proteins. In addition, the invention provides novel methods for producing target proteins in vivo using fusion proteins containing conditional retention domains and methods for identifying novel CRDs.