Abstract: Solid substrate electrospray mass spectrometry is an ambient mass spectrometry method that involves carrying, ionization and detection of the samples. This approach has a wide range of applications, and which is appropriate for rapid mass spectrometric analyses of small molecules to large biological molecules. However, when dealing with targets existing at trace levels in complicated matrices, the sensitivity of solid substrate electrospray mass spectrometry is becoming more of an issue. The solid substrate is the most important component of a solid substrate electrospray ionization source, and its selectivity is critical for improving the ionization efficiency and signal response of the target compound. The improvement of detection capability of trace components in complex samples by solid substrate electrospray mass spectrometry can be obtained by two strategies. On the one hand, to reduce the effect of matrix interference on detection sensitivity and collect as many target analytes as possible, on the other hand, to improve solvent desorption and target ionization efficiency in the electrospray solvent elution process to form electrospray. This review firstly summarized the variety of solid substrate materials, and then introduced the development strategies for improving the selectivity of ion source, such as ways for modifying solid substrates using carbon-based materials, polymers, and immunological materials, as well as their applications. Surface modification of solid substrates using functional compounds can improve the selectivity and adsorption of target analytes, reduce the matrix interference and improve the detection sensitivity. Finally, the benefits and drawbacks of various methods were explored, as well as the challenges and potential development tendencies.