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Since the initial discovery of universal stress protein A (UspA) 25 years ago, remarkable advances in molecular and biochemical technologies have revolutionized our understanding of biology. Many studies using these technologies have focused on characterization of the uspA gene and Usp-type proteins. These studies have identified the conservation of Usp-like proteins across bacteria, archaea, plants, and even some invertebrate animals. Regulation of these proteins under diverse stresses has been associated with different stress-response genes including spoT and relA in the stringent response and the dosR two-component signaling pathways. These and other foundational studies suggest Usps serve regulatory and protective roles to enable adaptation and survival under external stresses. Despite these foundational studies, many bacterial species have multiple paralogs of genes encoding these proteins and ablation of the genes does not provide a distinct phenotype. This outcome has limited our understanding of the biochemical functions of these proteins. Here, we summarize the current knowledge of Usps in general and UspA in particular across different genera as well as conclusions about their functions from seminal studies in diverse organisms. Our objective has been to organize the foundational studies in this field to identify the significant impediments to further understanding of Usp functions at the molecular level. We propose ideas and experimental approaches that may overcome these impediments and drive future development of molecular approaches to understand and target Usps as central regulators of stress adaptation and survival. Despite the fact that the full functions of Usps are still not known, creative many applications have already been proposed, tested, and used. The complementary approaches of basic research and applications, along with new technology and analytic tools, may yield the elusive yet critical functions of universal stress proteins in diverse systems.