In this Account we describe recent advances in two ab initio electronic structure methods, localized perturbation approaches and density functional theory, that allow accurate calculations including electron correlation to be carried out for systems with hundreds of atoms. Application of these methods to large-scale modeling of biological systems is discussed. Localized perturbation methods are best suited to computation of conformational energetics and nonbonded interactions: determination of the relative energetics of various conformations of the alanine tetrapetide is presented. Density functional theory is the method of choice for studying reactive chemistry; investigations of the catalytic cycle of the enzyme methane monooxygenase are reviewed.