Given the general availability and accessibility of extensive databases of reference spectra, the GC-MS techniques with electron ionization (EI) continue to be more useful in identifying xenobiotics and in screening analyses in contrast to LCMS techniques, which are predominantly used in targeted analyses and quantification; however, the increasingly frequent use of tandem fragmentation and new types of mass analyzers has led to an increase in LC-MS in screening analyses, especially when targeting compounds associated with a particular problem. The high sensitivity of these analyzers allows simultaneous detection and determination of numerous substances at low concentrations and in a small amount of biosample. When developing screening methods for various compounds, universally accepted international criteria should be respected. It is only when such criteria are met that the results are reliable in ruling out or confirming the presence in a biosample of even very rare xenobiotics included in the analytical range. These techniques correctly applied can also be used to determine the concentration values in relation to therapeutic use of a substance, overdosage, or abuse of a given substance. This article describes GS-MS and LC-MS techniques as well as inductively coupled plasma with optical emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectroscopy (ICP-MS). The latter two techniques permit the analysis of approximately 70 elements in a single analytical process. 2 tables and 28 references