Commonly, a limited number of generally accepted bulking agents and lyoprotectants are used for freeze-drying; predominantly mannitol, glycine, sucrose and trehalose. The purpose of this study was to combine a theoretical approach using molecular descriptors with a large scale experimental screening to evaluate the suitability of a broad range of excipients for freeze-drying. A large selection of sugars, polyols and amino acids was characterized by modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD) after well-plate based freeze-drying. The calculated molecular descriptors were investigated with both hierarchical cluster analysis and principal component analysis. A clear clustering of the excipients according to the size-related and weight-related descriptors was observed; however other relevant descriptors could also be identified. From a practical perspective, a trend was observed with regard to a higher likelihood for amorphisation and a higher glass transition temperature of the maximally freeze-concentrated solution with increasing molecular size. A translation of the molecular descriptors on pharmaceutical performance was more successful for lyoprotectants than for bulking agents. Additionally, in the course of the experimental screening, several new potential bulking agents and lyoprotectants were identified.