Mechanotransduction from the extracellular matrix into the cell is primarily supervised by a transmembrane receptor, integrin, and a cytosolic protein, talin. Integrin binds ligands on the extracellular side, whereas talin couples integrin receptors to the actin cytoskeleton and later acts as a "force buffer". Talin and integrin together form a mechanosensitive signaling hub that regulates crucial cellular processes and pathways, including cell signaling and formation of focal adhesion complexes, which help cells to sense their mechano-environment and transduce the signal accordingly. Although both proteins function in tandem, most literature focuses on them individually. Here, we provide a focused review of the talin-integrin mechano-interactome network in light of its role in the process of mechanotransduction and its connection to diseases. While working under force, these proteins drive numerous biomolecular interactions and form adhesion complexes, which in turn control many physiological processes such as cell migration; thus, they are invariably associated with several diseases from leukocyte adhesion deficiency to cancer. Gaining insights into their role in the occurrence of these pathological disorders might lead us to establish treatment methods and therapeutic techniques. © 2019 American Chemical Society.