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Determining structures of membrane proteins remains a significant challenge. A technique utilizing high lipid–detergent concentrations (“HiLiDe”) circumvents the major bottlenecks of current membrane protein crystallization methods. During HiLiDe, the protein–lipid–detergent ratio is varied in a controlled way in order to yield initial crystal hits, which may be subsequently optimized by variation of the crystallization conditions and/or utilizing secondary detergents. HiLiDe preserves the advantages of classical lipid-based methods, yet is compatible with both the vapor diffusion and batch crystallization techniques. The method has been applied with particular success to P-type ATPases.