The advent of UPLC (known more widely as U-HPLC) brought with it the prospect of achieving high efficiencies through the use of sub-2 µm particles but it has been used more to achieve fast separations using short columns. It was therefore sought to assess whether the efficiency obtainable on such short columns was sufficient for a range of pharmaceutical applications involving active pharmaceutical ingredients (APIs) Mobile phase optimization was required, but this could be done very quickly without resorting to computer-aided strategies. It proved possible to separate paroxetine from its related substances in under 1.2 min, to reduce by 1/10th the time needed for a routine QC assay, to rapidly develop conditions employing on-column sample focusing that allowed the separation and detection of low levels of ‘worst-case scenario’ drugs that might be involved in cleaning validation, and, using a longer column, achieve a rapid separation of benzodiazepines suitable for an identity test. While mobile phase optimization could be carried out quickly to produce very fast separations, it was clear from the benzodiazepine example, in particular, that there is still scope in UPLC for employing longer columns and/or stationary phase selectivity other than that offered by C18-silicas.