This article describes the challenges and solutions that have been realized during the last 10 years by a number of clinical laboratories that have embraced automation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) technologies for clinical utility. Current state-of-theart liquid handling-based sample preparation, multiplexed chromatographic systems, and automated data review technologies are described, facilitating more than 2500 samples per system per day. Emerging technologies are discussed that may fundamentally drive the application of systems solutions for mass spectrometry to a broader clinical setting. Copyright © 2011 by Elsevier Inc.