Ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS) variants currently represent the best tools to tackle the challenges of complexity and lack of comprehensive coverage of the metabolome. UHPLC offers flexible and efficient separation coupled with high-sensitivity detection via HRMS, allowing for the detection and identification of a broad range of metabolites. Here we discuss current common strategies for UHPLC-HRMS-based metabolomics, with a focus on expanding metabolome coverage.