Genetic and environmental factors, including exposure to toxic and bio-active chemicals play a pivotal role in the development of many diseases . Despite the importance of nongenetic risk factors in disease etiology, the chemical exposome is still poorly understood. In addition, covering a wide and diverse chemical space in a highly-sensitive manner has several limitations. One bottleneck is often the lack of sensitivity in high-resolution mass spectrometry assays (HRMS) compared to the highly-specific targeted triple-quadrupole (QQQ) approaches . As only a limited number of chemicals/chemical groups are encompassed by such tailored, targeted approaches, a postanalysis search for unknown analytes is not feasible. Thus, the application of low-resolution targeted methods is restricted in exposome-type research . With HRMS, however, the detection and quantification of low-abundance chemicals is impacted because the instrument's sensitivity often falls below that of low-resolution mass spectrometers. The problem is exacerbated by the presence of dominant high-abundance peaks that typically originate from endogenous metabolites and other interferences . As exogenous compounds are usually present at low concentrations in the human body, a reduced sensitivity hinders the detection of a certain portion of the chemical exposome. Additionally, poor ionization efficiency can further hamper the analysis. It is known that concentrations of endogenous and exogenous compounds in biological matrices (e.g., human plasma) can span eight to eleven orders of magnitude . Pharmaceuticals and many food constituents are present in concentrations similar to endogenous metabolites, however, chemicals such as pesticides and plasticizers and natural contaminants are approximately 400-700 times lower in mean concentration. Detection of such analytes requires therefore a high sensitivity and highlights the need for highlysensitive LC-HRMS approaches . Recently, HRMS was used in exposome-wide association studies (ExWAS) to decipher chemicals associated with disease aetiology, e.g., allergy-related outcomes , child cognitive function , childhood obesity , and semen quality . Nevertheless, targeted lowresolution methods are still widely used to capture specific areas of the chemical exposome . The combination of both approaches has been recommended . A systematic and thorough comparison between high-resolution instrumentation and triple quadrupole tandem mass spectrometry has only been described for individual analyte groups, e.g., polybrominated diphenyl ethers in fish , clinically-relevant compounds in plasma , illicit drugs in wastewater , and cathinones in urine . Uniformly, these studies indicated similar or better sensitivity of low-resolution instruments. This study aimed to determine the disparity between the limit of quantitation (LOQ) of a high-resolution instrument and a triple quadrupole mass spectrometer, both operated in their typical acquisition mode. In this study, the LOQ was not only estimated in pure solvent but also in spiked urine samples. The evaluation included >100 xenobiotics and estrogens from various sources. Following the Eurachem Guideline 2014 (EuraChem 2014), the LOQ was estimated by calculating the standard deviation of multiple injections of a low concentration standard. Moreover, the ability of both approaches to detect analytes at naturally occurring concentrations was demonstrated in urine samples.