New developments in the high throughput purification of combinatorial libraries by automated preparative LC-MS is presented. To facilitate high speed purifications at the multimilligram level, short columns operated at ultra high flow rates were incorporated. In order to match the linear velocity of the short analytical columns for high speed separations (operated at 4.0 mL/min), it was required to operate the preparative columns at flow rates in excess of 70 mL/min. For chromatographically well-behaved compounds, analytical LC-MS analyses and preparative LC-MS analyses could be achieved in as little as 5 min. For compounds exhibiting poor chromatographic peak shapes and/or for compound mixtures requiring higher resolution separations, slightly longer preparative LC-MS analysis times were required (8-10 min/sample). Fraction collection based on mass-triggering (as opposed to UV triggering) is an exquisitely sesitive and selective technique for purifying combinatorial libraries. However, because of its inherent selectively ( i.e; only the predicted synthetic product is isolated), synthetic by-products or other explainable reaction products are ignore during the purification process. In some instances especially if the structure of these synthetic by- products is known ( or can be elucidated readily), these compounds might and should be isolated for biological testing as well, PreplCMS purifications in our laboratory have been achieved using Applescripting as a way to permit communication between the mass spectrometer and the fraction collector. This Applescript was modified to permit the input of up to four unique ( +/ or same ) masses in the data acquisition software to permit purification of up to four compounds from a single run. This was demonstrated for a combinatorial library synthesized in a microtiter plate and purified directly into a fraction collector containing four deep-well microtiter plates, making these purified microtiter plates amenable to direct biological screening.