The genetic modification of recombinant proteins to include affinity tags can greatly simplify their purification. A key drawback to this technology has been the difficulty and expense associated with the removal of the tag from the purified product. In this work, we review the development and application of an engineered self-cleaving module that can be used to generate convenient self-cleaving tags. Further, we describe the use of this module with conventional affinity and non-chromatographic purification tags, which allow purification of native proteins through simple and inexpensive means. Limitations to these technologies are also discussed, along with some perspectives on the short-term future development of these methods.