The insertion of transgenes into the plastid genome (plastome) has proved to be an effective alternative to nuclear transformation for producing stable transformants expressing heterologous proteins. Recently, methodology, characteristics, and possible fields of application of plastome transformation have been extensively reviewed (Lössl and Waheed, 2011; Scotti et al., 2012). From these reports, plastid transformation turns out to be a very promising tool for the production of recombinant proteins in plants, yet some limitations must still be overcome. Although the plastome of many species has been successfully transformed, an efficient and reproducible transformation procedure easily adoptable by any plant laboratory has been established only in tobacco (Nicotiana tabacum) and to a minor extent in two other solanaceous species (potato [Solanum tuberosum] and tomato [Solanum lycopersicum]) as well as in a few other species (Maliga and Bock, 2011). Moreover, up to now, the steady-state level of a recombinant protein coded by a gene inserted into the plastome has failed to be predictable. In spite of a huge number of reports on successful foreign protein production in plastids, above all proteins with a pharmaceutical interest, in many cases the expression level of other recombinant proteins in the transplastomic plants appears to be very low or even undetectable (Birch-Machin et al., 2004; Bellucci et al., 2005; Wirth et al., 2006). We believe that this is mainly due to our limited knowledge of the mechanisms in plastids influencing the maintenance of protein homeostasis, or proteostasis. This term refers to a complex network of biological pathways capable of maintaining the dynamic equilibrium of the protein pool, thus allowing the cell to get used to environmental changes (Balch et al., 2008). This concept can also be extended to the subcellular level, especially for those organelles with an endosymbiotic origin like the plastids and mitochondria (Waller, 2012). These organelles retain a whole series of mechanisms for the preservation of their protein balance, including specific proteases, transcriptional and translational control, as well as molecular chaperones and enzymes useful in protein folding. Therefore, it is important to develop basic studies in factors regulating protein synthesis, stability, folding, targeting, and accumulation in plastids, including the protein quality control that contributes to the functional integrity of proteins. Our intention here is not to provide a comprehensive review of the mechanisms that regulate plastid proteostasis but to discuss some recent insights into this field that might bring beneficial applications in plastid biotechnology for transgene expression and foreign protein accumulation.