Cells are organized into many different compartments such as the cytosol, nucleus, endoplasmic reticulum (ER), and mitochondria. Almost all proteins are made in the cytosol, yet each cellular compartment requires a specific set of proteins.  How does the cell regulate protein localization to be sure that proteins end up where they should? In his first lecture, Manu Hegde reviews the history of this field and highlights key experiments that have led to our current understanding of how protein localization occurs.