Two uncharged microcrystalline substances, pyrene (PYR) and fluorescein diacetate (FDA), were rendered water dispersible by treatment with various amphiphilic substances and subsequently encapsulated by exposure to an alternating sequence of cationic and anionic polyelectrolytes. The amphiphilic compounds employed to charge the microcrystals were ionic surfactants, phospholipids, and polyelectrolytes with an amphiphilic nature. Polyelectrolyte layers were self-assembled onto the pre-charged microcrystalline templates by means of electrostatic layer-by-layer deposition, thus forming a multilayered polymeric shell around the crystalline cores. The semipermeable nature of the polymer multilayer shell was thereafter exploited to remove the templated core by exposure to a mild organic solvent. The release behavior of solubilized PYR and FDA from the crystalline core was examined by monitoring their fluorescence after dissolution with ethanol. Complete removal of the core yielded hollow polymer capsules of micrometer dimensions. The capsule porosity was found to be influenced by the amphiphile used to pre-charge the microcrystal surface. The strategy presented is expected to be a general approach for the encapsulation of hydrophobic, low molecular weight compounds such as drugs, as well as providing a novel and facile pathway to the fabrication of polymer multilayered microcapsules with controlled release properties for drug delivery.