The crystalline sponge (CS) method was developed as an X-ray crystallographic molecular structure analysis method that can be performed without the need for crystallization of the analyte. CS has strong molecular-recognition properties and a highly flexible framework. The amount of analyte can be reduced to a sub-milligram level. These features of the crystalline nano-space allow for determining the absolute structure of a trace analyte. In this review, we focus on the discovery of the CS method and its applications to biosynthetic products in combination with NMR spectroscopy. We also describe some examples of the CS method that are used mainly in combination with mass spectrometry (MS). Both approaches demonstrate the potential of microanalysis to determine the molecular structure of an unknown sample. Finally, we mention the use of a crystalline "nano-surface" rather than a crystalline nano-space in MS, which can detect small metabolites as well as post-translation biomolecules.