Sorting of proteins for secretion from cells is crucial for normal physiology and the regulation of key cellular events. Although the sorting of lysosomal hydrolases at the trans-Golgi network (TGN) for delivery to pre-lysosomes is well characterized, the corresponding mechanism by which secreted proteins are sorted for plasma-membrane delivery remains poorly understood. Recent discoveries have revealed a novel sorting mechanism that requires the linkage between the cytoplasmic actin cytoskeleton to the membrane-anchored Ca²⁺ ATPase, SPCA1 (secretory pathway calcium ATPase 1), and the luminal 45kDa Ca²⁺-binding protein, Cab45, for successful sorting of a subset of proteins at the TGN. We review progress in understanding these processes.