With several instrument configurations available from various manufacturers, liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology is currently intensively studied for comprehensive drug screen and confirmation. An LC-MS/MS database, including 780 drug and toxic compounds, has been constructed, featuring information-rich MS/MS spectra derived from a novel fragmentation approach incorporating voltage ramping and broadened mass window for activation. The resulting spectra are rich in high- and low-mass fragment ions, highly effective for matching and proven reproducible over a 6 month test period. Coupled to effective sample preparation protocols, the database-searching process greatly improved the identification of drugs in postmortem specimens by the LC-electrospray ionization (ESI)-MS/MS technology. This method has significantly improved the efficiency of our routine laboratory operation that was based on a two-step [fluorescence polarization immunoassay (FPIA) and gas chromatography/mass spectrometry (GC/MS)] approach in the past.