Synthetic oligonucleotides are prepared via automated solid phase synthesis techniques on a variety of polymer and controlled-porosity glass (CPG) supports. While automation generally provides remarkably high yields of synthetic oligonucleotides, subsequent removal of the precious material from the solid support is plagued by degradation and low recovery and requires the use of several potentially hazardous reagents, e.g. concentrated ammonium hydroxide and methylamine. Given these limitations, our goal was to develop an alternative cleavage-deprotection protocol for highly modified synthetic oligonucleotides that is safe and robust. During our studies we have identified several problematic areas such as rapid degradation of specific nucleotides and slow removal of certain protecting groups. To combat this we have implemented a few creative solutions that eliminate these concerns yet allow for rapid throughput of a variety of synthetic oligonucleotide species. These refinements and strategies for this critical process will be presented.