The taxanes are among the most important cancer chemotherapy drugs approved for clinical use in the last two decades. Paclitaxel is used as first-line therapy for a variety of cancers, and numerous drug delivery approaches are under investigation to enhance its selectivity and effectiveness against tumors. One strategy is to produce sustained, low drug levels within the tumor to enhance apoptosis and inhibit angiogenesis. The interest in altering drug concentration/time exposure profiles to improve therapeutic outcomes creates the necessity to quantify low concentrations of paclitaxel in cells or tissues. Here, a selective solid phase extraction (SPE) method, coupled with a capillary liquid chromatography-tandem mass spectrometry (microLC-MS/MS) method, was developed to quantify low, therapeutically relevant concentrations of paclitaxel that could not be analyzed using conventional LC-MS/MS. Under optimized SPE wash and elution conditions, paclitaxel was selectively extracted from biological samples, and most matrix components were removed. A 150 x 0.5 mm ID ODS capillary column was used for microLC separation and the flow rate was 12 microL min(-1). Sample extracts were focused at the front of the microLC column and then eluted with a gradient. The lower limits of detection and quantification were 5 and 20 pg mL(-1), respectively, permitting quantification of paclitaxel in small tissue samples or in cultured cells exposed to low drug concentrations. The quantitative linear range was 20-20 000 pg mL(-1). The ability to quantify these low concentrations of paclitaxel provides an important tool to study the concentration-dependent pharmacological effects of this important drug.