Low production cost is a key factor driving the development of plants and plant tissue cultures for the synthesis of therapeutic and other foreign proteins. Because product yield and concentration exert a major influence on process economics, improving foreign protein accumulation is crucial for enhancing the commercial success of plant-based production systems. Strategies aimed at increasing transgene expression have been effective; however, a critical but poorly understood factor contributing to low foreign protein yield is post-synthesis and/or post-secretion instability and degradation. Loss of foreign protein as result of biological and physical processes such as proteolytic destruction and irreversible surface adsorption can occur in plants and plant culture systems. This review highlights the need to consider such mechanisms and outlines a range of remedial strategies aimed at minimizing foreign protein degradation and loss.