Mass spectrometry is a powerful analytical tool for determining the isotope ratios and concentrations of trace elements in various samples at levels ranging from major constituents to subparts per billion. Because isotope dilution is free from matrix effects, it has the potential of being incorporated into a definitive analytical approach that can provide reference values for concentrations in physiological and pathological conditions. In addition, isotope dilution mass spectrometry results are free from the constraints of quantitative recovery of the analyte, an essential requirement in other analytical techniques that is difficult to achieve with complex biological samples. A variety of mass spectrometric approaches have been used for determining the concentration of trace elements in biological samples. The more commonly used are thermal ionization mass spectrometry, inductively coupled plasma mass spectrometry, fast atom bombardment mass spectrometry, and gas chromatography mass spectrometry. This article reviews the work on trace element determination in biological samples using different mass spectrometric techniques and highlights the experiments performed by the authors in establishing gas chromatography mass spectrometry.