Laser-induced acoustic desorption (LIAD) enables the desorption of nonvolatile and/or thermally labile neutral compounds, such as asphaltenes, saturated hydrocarbons in base-oil fractions and biomolecules, from a metal surface into a mass spectrometer. This is a “gentle” evaporation technique and causes minimal fragmentation to the desorbed neutral molecules, including oligonucleotides and polypeptides. LIAD can be coupled with a wide range of ionization methods to facilitate analysis of the desorbed analytes by using many different types of mass spectrometers, including Fourier transform ion cyclotron resonance, linear quadrupole ion trap and quadrupole time-of-flight instruments. The development and improvement of LIAD remains an active research area with diverse goals such as better desorption efficiencies, minimized analyte fragmentation and greater versatility. This article details the theory, experimental methods, applications, and future directions of LIAD in combination with mass spectrometry.