For high-resolution x-ray crystallography, two bottlenecks must be overcome: First, enough protein of suitable quality must be produced, and, second, three-dimensional high-resolution crystals of sufficient size must be obtained. Crystal growth is kinetically and thermodynamically controlled and exhibits two phases, i.e. nucleation and crystal extension. The latter increases the size of nuclei to macroscopic dimensions. However, the optimal conditions for nucleation and crystal extension are in general different, making it notoriously difficult to obtain crystals of suitable size. Crystal nuclei or nano-crystals are tiny and assembled from just a few hundred proteins. They can be analyzed with electron microscopy (EM) by imaging and electron nano-diffraction (ND), but are too small and decay too fast for the analysis by classical X-ray beam-lines. However, the high intensity of femto-second x-ray free-electron (FEL) pulses will allow diffraction patterns to be recorded before the sample damage occurs.