In multicellular organisms, several biological processes control the rise and fall of life. Different cell types communicate and co-operate in response to different stimulus through cell to cell signaling and regulate biologic processes in the cell/organism. Signaling in multicellular organism has to be made very secretly so that only the target cell responds to the signal. Of all the biomolecules, nature chose mainly proteins for secret delivery of information both inside and outside the cell. During cell signaling, proteins physically interact and shake hands for transfer of secret information by a phenomenon called as protein–protein interactions (PPIs). In both, extra and intracellular signaling processes PPIs play a crucial role. PPIs involved in cellular signaling are the primary cause for cell proliferation, differentiation, movement, metabolism, death and various other biological processes not mentioned here. These secret handshakes are very specific for specific functions. Any alterations/malfunctions in particular PPIs results in diseased condition. An overview of signaling pathways and importance of PPIs in cellular function and possibilities of targeting PPIs for novel drug development are discussed in this review. © 2016, Higher Education Press and Springer-Verlag Berlin Heidelberg.