Two commonly encountered bottlenecks in the structure determination of a protein by X-ray crystallography are screening for conditions that give high quality crystals and, in the case of novel structures, finding derivatization conditions for experimental phasing. Brominated and iodinated phasing compounds I3C and B4C were added to crystallization screens and could be incorporated into growing crystals. The frequency of hit conditions leading to the formation of well-defined crystals could be further maximised through random microseed matrix screening (rMMS) to generate high quality crystals derivatised with phasing compound in a single optimization experiments. This approach was applied to efficiently phase the structure of hen-egg white lysozyme and the N-terminal domain of Orf11 protein from phage P68, a completely novel structure, using SAD phasing. Derivatisation of crystals using seeding with these phasing compounds represent a significant expansion to the crystallography arsenal, allowing efficient structure solution of novel proteins.