Systems and methods for imaging and ablating a sample

Disclosed herein are systems for imaging and ablating a sample. An imaging/ablating device includes an optical assembly, a sample stage, and a receiver. The optical assembly enables ablation of a region of interest within the sample. The laser light propagated from the optical assembly during ablation propagates substantially in the same direction as the direction of travel of the ablation plume toward the receiver. A laser focus detection unit including at least one reference laser and photodetector generates at least one real-time detection signal indicative of one or more characteristics of the sample during ablation and/or of a distance from the objective to the sample stage or a surface of the sample. A controller coupled with the laser focus detection unit dynamically controls in real-time one or more parameters of the ablation laser and/or a position of the objective and/or a position of the receiver relative to the sample to improve MS imaging quality.