After years of assessment through controlled clinical trials, low-dose CT screening for lung cancer is becoming part of clinical practice. As with any cancer screening test, those undergoing lung cancer screening are not being evaluated for concerning signs or symptoms, but are generally in good health and proactively trying to prevent premature death. Given the resultant obligation to achieve the screening aim of early diagnosis while also minimizing the potential for morbidity from workup of indeterminate but ultimately benign screening abnormalities, careful implementation of screening with conformance to currently recognized best practices and a focus on quality assurance is essential. In this review, we address the importance of each component of the screening process to optimize the effectiveness of CT screening, discussing options for quality assurance at each step. We also discuss the potential added advantages, quality assurance requirements and current status of quantitative imaging biomarkers related to lung cancer screening. Finally, we highlight suggestions for improvements and needs for further evidence in evaluating the performance of CT screening as it transitions from the research trial setting into daily clinical practice.