De novo and rational protein design are progressing towards the chemical synthesis of proteins with pre-selected structure and function. The data illustrate diverse experimental and computational approaches which test our comprehension of protein structure, hydrophobic core packing and global stability, especially of coiled-coil proteins. The incorporation of biological cofactors, including hemes, as well as active sites, such as that of iron superoxide dismutase, into designed proteins provides an exciting next step towards the synthesis of proteins with enzymatic function.