Poly(lactic acid) (PLA) and poly(lactic‐co‐glycolic acid) (PLGA) microspheres and nanoparticles remain the focus of intensive research effort directed to the controlled release and in vivo localization of drugs. In recent years engineering approaches have been devised to create novel micro‐ and nano‐particles which provide greater control over the drug release profile and present opportunities for drug targeting at the tissue and cellular levels. This has been possible with better understanding and manipulation of the fabrication and degradation processes, particularly emulsion‐solvent extraction, and conjugation of polyesters with ligands or other polymers before or after particle formation. As a result, particle surface and internal porosity have been designed to meet criteria‐facilitating passive targeting (e.g., for pulmonary delivery), modification of the drug release profile (e.g., attenuation of the burst release) and active targeting via ligand binding to specific cell receptors. It is now possible to envisage adventurous applications for polyester microparticles beyond their inherent role as biodegradable, controlled drug delivery vehicles. These may include drug delivery vehicles for the treatment of cerebral disease and tumor targeting, and codelivery of drugs in a pulsatile and/or time‐delayed fashion. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:71–87, 2008