The rapid and precise chemical characterization of complex mixtures of small molecules is essential for contemporary natural products’ (Nps) research, as well as for the quality control of herbal medicines and dietary supplements. While LC-MS is generally considered as method of first choice to meet these analytical challenges, the current work will present matrix free laser desorption ionization (LDI) as a versatile supplement or potential alternative to this approach [1], [2]. Among others, particularly phenolic NPs exhibit close structural similarities to matrices used in matrix assisted laser desorption ionization. Consequently, these compounds may be ionized by laser irradiation without matrix support. This concept is being outlined by two examples: The first focuses on the chemical profiling of propolis obtained from different global regions, where high resolution LDI-MS permitted the identification of 34 compounds (mostly cinnamic acid and flavonoid derivatives) from a crude extract of French propolis. A contemporaneously performed LC-ESI-MS experiment solely detected 23 of these compounds. Moreover, LDI-MS facilitated the differentiation of propolis samples according to their origin by principal compound analysis (PCA). The second example discusses the LDI-monitoring of the metabolic profiles of apple seedlings (Malus x domestica) after being treated with various elicitors. Selected plants were further infected by Erwinia amylovora, the causative agent of fire blight. Again LDI-MS permitted the detection of key-metabolites (e.g. caffeic acid, phloridzin, and quercitrine) and also facilitated PCA grouping according to the applied treatment. These results highlight the interesting prospective of LDI-MS as powerful analytical tool and supplement to existing methods.