High-performance liquid chromatography coupled with mass spectrometry (LC-MS) has become a predominant analytical technique due to the orthogonal detection dimension that provides exceptional sensitivity, selectivity, and high throughput capabilities. However, matrix effects present a significant challenge, particularly when employing electrospray ionization (ESI) for the analysis of complex matrix extracts. Matrix effects manifest either signal suppression (decreased response) or signal enhancement (increased response), both of which significantly compromise analytical method performance. This networking focuses on recent advancements in LC-MS technology, the causes of matrix effects, and evaluates current strategies for their assessment and mitigation.