This paper reviews the clinical applications of tandem mass spectrometry (MS-MS) in diagnosis and screening for inherited metabolic diseases in the last 10 years. The broad-spectrum of diseases covered, specificity, ease of sample preparation, and high throughput provided by the MS-MS technology has led to the development of multi-disorder newborn screening programs in many countries for amino acid disorders, organic acidemias, and fatty acid oxidation defects. Issues related to sample acquisition, sample preparation, quantification of metabolites, and validation are discussed. Our current experience with the technique in screening is presented. The application of MS-MS in selective screening has revolutionized the field and made a major impact on the detection of certain disease classes such as the fatty acid oxidation defects. New specific and rapid MS-MS and LC-MS-MS methods for highly polar small molecules are supplementing or replacing some of the classical GC-MS methods for a multitude of metabolites and disorders. New exciting applications are appearing in fields of prenatal, postnatal, and even postmortem diagnosis. Examples for pitfalls in the technique are also presented.