p66Shc, a member of the ShcA (Src homologous- collagen homologue) adaptor protein family, is one of the three isoforms of this family along with p46Shc and p52Shc. p66Shc, a 66 kDa protein is different from the other isoforms of the ShcA family. p66Shc is the longest isoform of the ShcA family. p66Shc has an additional CH domain at the N-terminal, called the CH2 domain, which is not not present in the other isoforms. This CH2 domain contains a very crucial S36 residue which is phosphorylated in response to oxidative stress and plays a role in apoptosis. Whereas p52Shc and p46Shc are ubiquitously expressed, p66Shc shows constrained expression. This adaptor protein has been shown to be involved in mediating and executing the post effects of oxidative stress and increasing body of evidence is pinpointing to its role in carcinogenesis as well. It shows proto-oncogenic as well as pro-apoptotic properties. This multitasking protein is involved in regulating different networks of cell signaling. On one hand it shows an increased expression profile in different cancers, has a positive role in cell proliferation and migration, whereas on the other hand it promotes apoptosis under oxidative stress conditions by acting as a sensor of ROS (Reactive Oxygen Species). This paradoxical role of p66Shc could be attributed to its involvement in ROS production, as ROS is known to both induce cell proliferation as well as apoptosis. p66Shc by regulating intracellular ROS levels plays a crucial role in regulating longevity and cell senescence. These multi-faceted properties of p66Shc make it a perfect candidate protein for further studies in various cancers and aging related diseases. p66Shc can be targeted in terms of it being used as a possible therapeutic target in various diseases. This review focuses on p66Shc and highlights its role in promoting apoptosis via different cell signaling networks, its role in cell proliferation, along with its presence and role in different forms of cancers.