Liquid chromatography-mass spectrometry (LC-MS) is one of the most widely used analytical tools. High analysis volumes and sample complexity often demand more informative LC-MS acquisition schemes to improve efficiency and throughput without compromising data quality, and such a demand has been always hindered by the prerequisite that a minimum of 13-20 MS scans (data points) across an analyte peak are required for accurate quantitation. The current study systematically re-evaluated and compared the impact of different scan numbers on quantitation analysis using both triple quadrupoles mass spectrometry (TQMS) and high-resolution mass spectrometry (HRMS). Contrary to the 13-20 minimal scan prerequisite, the data obtained from a group of eight commercial drugs in the absence and presence of biological matrices suggest that 6 scans per analyte peak are sufficient to achieve highly comparable quantitation results compared to that obtained using 10 and 20 scans, respectively. The fewer minimal scan prerequisite is presumably attributed to an improved LC system and advanced column technology, better MS detector, and more intelligent peak detection and integration algorithms leading to a more symmetric peak shape and smaller peak standard deviation. As a result, more informative acquisition schemes can be broadly set up for higher throughput and more data-rich LC-MS/MS analysis as demonstrated in a hepatocyte clearance assay in which fewer MS scans executed on HRMS led to broader metabolite coverage without compromising data quality in hepatic clearance assessment. The demonstrated acquisition scheme would substantially increase the throughput, robustness, and richness of the nonregulatory analysis, which can be broadly applied in diverse fields including pharmaceutical, environmental, forensic, toxicological, and biotechnological.