Insoluble or even low solubility materials frequently present nearly insurmountable analytical challenges. Cell extraction is one such example. After cell opening, several extractions are carried out using different conditions and solvents. A residual “pellet” is obtained containing the insoluble fraction of the cell extract. This “pellet” is discarded because of the lack of appropriate analytical technology for analyses. (1,2) Other examples, such as phospholipids and phosphopeptides, can be solubilized and successfully extracted, but have an extreme tendency to adhere to column materials and are lost during attempts at purification (Scheme 9.1).(3-8) Perhaps the most well-known examples are membrane proteins that are poorly soluble or entirely insoluble if extracted from their native environment. Less than 1% of known protein structures are membrane proteins(9) even though it is estimated that 20-30% of the human genome encodes for them.(10,11) This, along with, for example, the production and deposition of insoluble plaques formed by β-amyloid peptides from amyloidprecursor protein (APP) limit our understanding of Alzheimer’s disease as is the case with many age-related diseases.(12) Future success is anticipated in discovering novel means to characterize insoluble materials on a molecular level in order to relate molecular structure to biological, chemical, or physical processes.(9,13-21) There is also a pressing need for rapid analysis of structurally, chemically, and dynamically complex systems, especially those of unadulterated tissue sections.