In the laboratory, zein microspheres are being investigated as drug/vaccine delivery systems. Preliminary experiments revealed that the release of an entrapped solute (ovalbumin, a model antigen) was limited when particles were incubated in phosphate buffered saline over a number of days. To understand the slow and limited release of the guest molecule and predict microsphere fate in vivo, the degradation of zein microspheres in different media, in the presence and in the absence of enzymes, was investigated in vitro. Zein microspheres were incubated in five different media: Chloride Buffer (pH 2), Acetate Buffer (pH 5), Phosphate Buffered Saline (pH 7.4), gastric simulated fluid and gastro-intestinal simulated fluid for 1 week. Changes in suspension turbidity and pH, microsphere morphology and zein composition in the release medium was followed with time. The results showed that zein microspheres were extremely resistant to degradation in the absence of enzymes (which explains the slow release of entrapped solute), but were degraded by pepsin and pancreatin enzymes in simulated gastric and intestinal fluids, respectively (which indicates that release is likely to be much faster following oral microsphere administration). However, when administered via routes where enzymes are not present, e. g. intra-muscular, release is likely to be slow.