The development of laser-based tissue microdissection systems has provided the basis for the rapid acquisition of specific morphologically and/or phenotypically distinct types of cells for many types of molecular analysis. Two laser microdissection technologies based on distinct principles have been developed, namely: laser capture microdissection and laser cutting microdissection. This commentary will outline the principles of each system and indicate their main advantages and potential drawbacks. Also discussed will be methods of cell and tissue preparation with particular reference to fixation and staining, which are crucial to both successful laser-based microdissection and also downstream molecular studies. Laser microdissection techniques are powerful technologies which combine morphology and histochemistry with sophisticated molecular analysis. Through their appropriate application they have provided significant new insights into cell biology and pathology.