The 252Cf-PDMS method is a 'mature' technique, having survived 20 years of research, development and application. Recent advances in the application of the method have led to the use of the technique in clinical quantitation studies, the development of a microscopic method for measuring chemical homogeneity, in situ applications where serial modifications can be made and studied in a sequential fashion and the utilization of the primary fragmentation patterns to correlate with primary structure. Future directions in research, development and application will focus more attention on the chemistry of the 252Cf-PDMS process and the understanding and control of gas-phase reactions that occur in the ejection plume. Predictions are that the application of the in situ modification technique could lead to a new approach to pharmacokinetic studies as well as cell surface interactions where 252Cf-PDMS is effectively used to expand the capabilities of in vitro studies of biological processes.