The highly specialized field of inborn errors of metabolism (IEM) goes hand in hand with laboratory medicine. Diagnosis and therapeutic monitoring of many IEMs require indeed highly specialized laboratory analyses that are only available in tertiary care and academic hospital facilities. Medical expertise regarding these orphan diseases is also often scarce outside specialized IEM reference centers. A few basic laboratory tests, that are widely available in most hospitals, may however give important hints to suspect an underlying IEM in “unusual” clinical situations. Thus, biochemical pathways governing the interplay of key intermediates of energy metabolism that are glucose, ketones and lactate are reviewed, as well as pathways influencing more organ specific biomarkers, such as ammonium, creatine kinase, homocysteine and uric acid. Clinical indications to prescribe each of these laboratory analyses and adequate handling of the biological samples are reviewed, since these are prerequisites to providing meaningful test results. The importance of following laboratory medicine good practice rules is discussed, since the increasing burden of overall medical costs puts pressure on physicians to optimize the way they request and interpret laboratory results. Examples of published algorithms that assist these processes will be shown, highlighting clinical and para-clinical constellations in which an underlying IEM should be suspected. Biochemistry is taught during the preclinical years of medical training but often neglected during further professional education. IEMs illustrate the links between basic sciences, clinical reasoning and treatment options in an outstanding, logical way. In order to illustrate the educational value of these rare “orphan” diseases, a few treatable IEMs that should come to mind when patients display abnormal results in the aforementioned common clinical biomarkers will be described. The field of IEMs is complex and requires very sophisticated laboratory tools; however, a sound knowledge of a few essential metabolic pathways and simple laboratory tools should allow any primary care physician to suspect a possible underlying IEM and take appropriate steps for further management and referral.