p66^Shc is a 66 kDa Src homology 2 domain containing (Shc) adaptor protein homolog. Previous studies have demonstrated that p66^Shc is a proapoptotic protein involved in the cellular response to oxidative stress and in regulating mammalian lifespan. However, accumulating evidence also indicates its critical role in solid tumor progression. The expression of p66^Shc varies in different types of solid tumors, and it can paradoxically promote as well as suppress tumor progression, survival, and metastasis, depending on the cellular context. In this review, we discuss its functions in various solid tumors, the mechanisms by which it mediates the process of anoikis (detachment-induced cell death), and the epigenetic mechanisms that regulate its expression. These studies indicate the potential of p66^Shc as a novel prognostic marker and therapeutic target for the prevention of tumor progression and metastasis.