Poly(lactide-co-glycolide) (PLGA) microspheres are efficient delivery systems for controlled release of low molecular weight drugs as well as therapeutic macromolecules. The most common microencapsulation methods are based on emulsification procedures, in which emulsified droplets of polymer and drug solidify into microspheres when the solvent is extracted from the polymeric phase. Although high encapsulation efficiencies have been reported for hydrophobic small molecules, encapsulation of hydrophilic and/or amphiphilic small molecules is challenging due to the partitioning of drug from the polymeric phase into the external phase before solidification of the particles. This review addresses formulation-related aspects for efficient encapsulation of small hydrophilic/amphiphilic molecules into PLGA microspheres using conventional emulsification methods (e.g., oil/water, water/oil/water, solid/oil/water, water/oil/oil) and highlights novel emulsification technologies such as microfluidics, membrane emulsification and other techniques including spray drying and inkjet printing. Collectively, these novel microencapsulation technologies afford production of this type of drug loaded microspheres in a robust and well controlled manner.