The article reviews the role of Hsp70 chaperones and their cofactors, particularly J-proteins (also known as Hsp40s), in various cellular processes. Hsp70s are essential molecular chaperones that regulate protein folding, degradation, and translocation across membranes. Despite their biochemical similarity, Hsp70s exhibit diverse functions due to the presence of J-proteins, which act as drivers of functional specificity. J-proteins often work in concert with multiple Hsp70s and nucleotide exchange factors (NEFs) to modulate Hsp70 activity. The J-domain, a conserved region in J-proteins, stimulates Hsp70's ATPase activity, facilitating client protein binding and release. The article discusses the canonical model of Hsp70 function, where J-proteins deliver clients to Hsp70 and NEFs promote client dissociation. However, the importance of client protein binding is highlighted in various cellular functions, including protein folding, degradation, and remodeling of folded proteins. The diversity of J-proteins and their structural variations are also explored, emphasizing their role in driving the multifunctionality of Hsp70 machinery. Additionally, the article touches on the role of NEFs in Hsp70 multifunctionality and the importance of chaperone partnerships beyond the core Hsp70 machinery. Finally, the authors discuss the potential for practical applications of targeting J-proteins in disease intervention.The article reviews the role of Hsp70 chaperones and their cofactors, particularly J-proteins (also known as Hsp40s), in various cellular processes. Hsp70s are essential molecular chaperones that regulate protein folding, degradation, and translocation across membranes. Despite their biochemical similarity, Hsp70s exhibit diverse functions due to the presence of J-proteins, which act as drivers of functional specificity. J-proteins often work in concert with multiple Hsp70s and nucleotide exchange factors (NEFs) to modulate Hsp70 activity. The J-domain, a conserved region in J-proteins, stimulates Hsp70's ATPase activity, facilitating client protein binding and release. The article discusses the canonical model of Hsp70 function, where J-proteins deliver clients to Hsp70 and NEFs promote client dissociation. However, the importance of client protein binding is highlighted in various cellular functions, including protein folding, degradation, and remodeling of folded proteins. The diversity of J-proteins and their structural variations are also explored, emphasizing their role in driving the multifunctionality of Hsp70 machinery. Additionally, the article touches on the role of NEFs in Hsp70 multifunctionality and the importance of chaperone partnerships beyond the core Hsp70 machinery. Finally, the authors discuss the potential for practical applications of targeting J-proteins in disease intervention.