Pre-analytical quality in clinical chemistry testing is as important as analytical and post-analytical quality. The most prevalent pre-analytical interference and a major source of error producing unreliable laboratory test results is hemolysis of blood samples. In vitro hemolysis may be due to the blood withdrawal technique or sample handling whereas in vivo hemolysis can originate from acquired, hereditary, or iatrogenic conditions and is not technique dependent. Interpreting in vivo or in vitro hemolysis requires clinicians to supply reliable clinical history and findings. Even then, to reject or release the result with interpretation is still under debate. Thus, hemolyzed specimens are a serious pre-analytical problem calling for well-designed and strictly implemented laboratory guidelines. The aim of this non-systematic review (addressed to healthcare professionals) was to highlight the challenges in identifying and rejecting hemolysis specimens.