Cell biologists have undergone a fundamental revision in their thinking in the past 20 years, with the realization that cells are far more elegant and efficient than was previously believed. We now appreciate that there is a great deal of redundancy built into cellular physiology: if a biological function is truly key to the survival of the cell, then there is usually more than one molecule able to serve that function. Similarly, many cellular proteins have evolved a high degree of versatility and are able to serve different purposes in different cellular contexts. For proteins that have been discovered only recently, the idea of multifunctionality is easy to swallow, but many classic cytoskeletal proteins were identified in an earlier time, when the simplistic “one protein, one function” view held sway. α-Actinin is one such protein; or rather, α-actinin is a family of four closely related gene products that were originally described as actin-crosslinking proteins. In the past few years, an accumulating body of literature has revealed that α-actinin possesses an exceptionally large number of molecular partners, in addition to actin (see Table I). Furthermore, α-actinin is present in multiple subcellular regions, including cell-cell and cell-matrix contact sites, cellular protrusions, lamellipodia and stress fiber dense regions. Thus, it is now clear that α-actinin plays multiple important roles in the cell: it links the cytoskeleton to many different transmembrane proteins in a variety of junctions, it regulates the activity of a variety of receptors, and it serves as a scaffold to connect the cytoskeleton to diverse signaling pathways. This review will discuss recent advances that highlight the expanding role of this molecule and the pathways that regulate its activities, with a particular focus on α-actinin’s functions in non-muscle cells.