Quality assurance monitoring of the LC-MS/MS testing process is required to ensure accuracy and reliability of patient results. Few resources are available that provide comprehensive guidelines for development, validation, and implementation of quality assurance metrics for LC-MS/MS assays. This chapter will present practical guidance on selecting and evaluating quantitative quality assurance metrics. Approaches for utilizing professional practice recommendations and data-driven techniques for the design and optimization of the laboratory’s quality assurance program will be discussed.