In addition to his contributions to synthetic organic chemistry, Clark Still was an early pioneer in applying computational methods to the study of organic compounds. Conformational analysis was integral to Stills study of macrocyclic stereocontrol, and there was a general need for a fast and reliable computational method for predicting an organic molecules lowest energy conformation.  In order to address the problem, Still and coworkers reported a simple Monte Carlo method for searching conformational space in 1989.  In this procedure, the internal coordinates for an organic molecule were varied at random, and the energy of the lowest energy conformation was determined after structure minimization.  After each iteration, the minimum energy was compared to the values obtained previously in order to locate the global minimum; Still referred to this overall process as a Monte Carlo multiple-minimum search.
In an effort to make molecular modeling more accessible to practicing organic chemists, Still developed the integrated software program MacroModel in 1986 in association with Columbia University.  Dr. Wayne Guida, a senior postdoctoral researcher in Still's group at the time, described the development of this software package in the following way: 
One particularly notable feature of MacroModel was the inclusion of an implicit solvation model known as GB/SA (generalized Born model augmented with the hydrophobic solvent accessible surface area term).  The GB/SA model simulated solvent interactions with organic molecules by incorporating a continuous solvent field instead of including explicit individual solvent molecules in the computation.  Still disclosed a full description of MacroModel in the Journal of Computation Chemistry in 1990, and the rights to this software were later acquired by Schrodinger, Inc. in 1998.