A key step in many approaches to crystal structure prediction (CSP) is the initial generation of large numbers of candidate crystal structures via the exploration of the lattice energy surface. By using a relatively simple lattice energy approximation, this global search step aims to identify, in a computationally tractable manner, a limited number of likely candidate structures for further refinement using more detailed models. This paper presents an effective and efficient approach to modeling the effects of molecular flexibility during this initial global search. Local approximate models (LAMs), constructed via quantum mechanical (QM) calculations, are used to model the conformational energy, molecular geometry, and atomic charge distributions as functions of a subset of the conformational degrees of freedom (e.g., flexible torsion angles). The effectiveness of the new algorithm is demonstrated via its application to the recently studied 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) molecule and to two molecules, β-d-glucose and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione, a Bristol Myers Squibb molecule referenced as BMS-488043. All three molecules present significant challenges due to their high degree of flexibility.