Signaling domains have been identified by the analysis of data derived from biochemical studies, molecular cloning, or genetic studies. With the availability of genomic information from many organisms and the improved sensitivity in homology detection techniques, many new domains are being identified. In an attempt to understand biochemical and biological function of these domains, we have started a small-scale structural genomics, or structural biology with genomic approach. Two examples from our recent work are steroidogenic acute regulatory protein (StAR)-related lipid-transfer (START) domain and inositol polyphosphate 5-phosphatase catalytic (IPP5C) domain. Crystal structure of human MLN64-START domain revealed a hollowed-out protein containing a hydrophobic tunnel just large enough to bind one molecule of cholesterol and completely exclude it from solvent. This structure suggests that the START domain is a classical type of lipid transporter. On the contrary, the function of IPP5C domain has been extensively studied for a long time, but its catalytic mechanism, positional selectivity, and diverse substrate specificity remained mysterious due to the unavailability of three-dimensional structure. With the structural genomic approach, the first structure of IPP5C domain was solved from a S. pombe protein that is now known as SPsynaptojanin and the structure gave us answers to some of these questions.