Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a wide range of protein folding processes by transiently associating with short hydrophobic peptide segments within their substrate proteins. The ATPase cycle of Hsp70, driven by the switching between the low-affinity ATP-bound state and the high-affinity ADP-bound state, is essential for their chaperone activity. This cycle is controlled by co-chaperones of the J-domain protein family and nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this cycle. For specific tasks, Hsp70s are coupled with other chaperone systems, such as Hsp90 and Hsp100. Hsp70s play crucial roles in de novo protein folding, refolding of misfolded proteins, and control of regulatory proteins. They prevent aggregation, promote folding to the native state, and solubilize and refold aggregated proteins. Hsp70s also interact with signal transduction pathways, influencing cell homeostasis, proliferation, differentiation, and cell death. In cellular physiology and pathophysiology, Hsp70s are involved in stress response and apoptosis, with overexpression leading to increased resistance against apoptosis-inducing agents. The mechanism of action of Hsp70s involves an ATPase domain and a substrate binding domain. The ATPase domain undergoes an alternating ATP and ADP state, with ATP hydrolysis being essential for chaperone activity. Co-chaperones like DnaJ and Bag proteins assist in ATP hydrolysis and substrate binding, respectively. The substrate binding domain has high sequence conservation and is crucial for recognizing and binding to specific peptide sequences. The coupling mechanism between the ATPase and substrate binding domains involves nucleotide-controlled opening and closing of the substrate binding cavity. Co-chaperones like J-domain proteins and Bag proteins target Hsp70s to specific substrates and mediate their release.Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a wide range of protein folding processes by transiently associating with short hydrophobic peptide segments within their substrate proteins. The ATPase cycle of Hsp70, driven by the switching between the low-affinity ATP-bound state and the high-affinity ADP-bound state, is essential for their chaperone activity. This cycle is controlled by co-chaperones of the J-domain protein family and nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this cycle. For specific tasks, Hsp70s are coupled with other chaperone systems, such as Hsp90 and Hsp100. Hsp70s play crucial roles in de novo protein folding, refolding of misfolded proteins, and control of regulatory proteins. They prevent aggregation, promote folding to the native state, and solubilize and refold aggregated proteins. Hsp70s also interact with signal transduction pathways, influencing cell homeostasis, proliferation, differentiation, and cell death. In cellular physiology and pathophysiology, Hsp70s are involved in stress response and apoptosis, with overexpression leading to increased resistance against apoptosis-inducing agents. The mechanism of action of Hsp70s involves an ATPase domain and a substrate binding domain. The ATPase domain undergoes an alternating ATP and ADP state, with ATP hydrolysis being essential for chaperone activity. Co-chaperones like DnaJ and Bag proteins assist in ATP hydrolysis and substrate binding, respectively. The substrate binding domain has high sequence conservation and is crucial for recognizing and binding to specific peptide sequences. The coupling mechanism between the ATPase and substrate binding domains involves nucleotide-controlled opening and closing of the substrate binding cavity. Co-chaperones like J-domain proteins and Bag proteins target Hsp70s to specific substrates and mediate their release.