The prevention of aberrant behavior of proteins is fundamental to cellular life. Protein homeostatic processes are present in cells to stabilize protein conformations, refold misfolded proteins, and degrade proteins that might be detrimental to the cell. Molecular chaperones and proteases perform a major role in these processes. In bacteria, the main cytoplasmic components involved in protein homeostasis include the chaperones trigger factor, DnaK/DnaJ/GrpE, GroEL/GroES, HtpG, as well as ClpB and the proteases ClpXP. ClpAP, HslUV, Lon, and FtsH. Based on recent genome sequencing efforts, it was surprising to find that the Mycoplasma, a genus proposed to include a minimal form of cellular life, do not contain certain major members of the protein homeostatic network, including GroEL/GroES. We propose that, in mycoplasmas, there has been a fundamental shift towards favoring processes that promote protein degradation rather than protein folding. The arguments are based on two different premises: (1) the regulation of stress response in Mycoplasma and (2) the unique characteristics of the Mycoplasma proteome. (C) 2003 Elsevier Inc. All rights reserved.