Here we detail a new platform, SCREEN, that improves upon the original SCoPE MS technique which had pioneered our ability to measure thousands of proteins in quantitative mode across many hundreds of single mammalian cells . This new platform, compared to the original, can quantify many more proteins per cell and is more sensitive to changes in protein abundance in single cells. Another advantage of SCREEN is its ability for much deeper proteome coverage, achieved by targeting specific parts of the proteome to detect slight differences in the cell proteome upon different drug treatment conditions, not possible by the original SCoPE MS.