Innovative methodologies, introduced in the software EXPO and working both in the reciprocal and in the direct space, can be successfully adopted for solving crystal structure by X-ray powder diffraction data. The principles underlying these methodologies are summarized. Three representative examples of crystal structure solution of the peptides Z-(Aib)2-OH, Z-(Aib)3-O-t-Bu and Z-(Aib)4-OH are discussed in relation to their different degree of structure complexity.