Alternatively to the well-consolidated liquid chromatography coupled to tandem mass spectrometry approach used for the evaluation of anticancer drug concentrations in treated patients, new mass spectrometric methods have been proposed and tested recently. They exhibited faster analysis time and, at first sight, simpler instrumental approaches. However, results obtained by these methods require an in-depth evaluation, because of their strong dependence on the experimental set-up. In this short review, the quantification of irinotecan, sunitinib, and 6-α-hydroxy paclitaxel (the main metabolite of paclitaxel) by laser desorption ionization techniques (matrix-assisted laser desorption/ionization, nanostructure-assisted laser desorption/ionization, and surface-assisted laser desorption/ionization) is reported and discussed, showing the advantages but also the drawbacks of the methods. The matrix-assisted laser desorption/ionization approach led to the most reliable results, and the cross-validation for the quantitative analysis of irinotecan indicates that this method can be fruitfully used for therapeutic drug monitoring and pharmacokinetic studies. Another recently proposed technique, paper spray mass spectrometry, has been tested for the quantitative measurement of imatinib in plasma samples. Even if the approach is, at first sight, really simple, the parameterization of the analytical and instrumental aspects has required many efforts to reach satisfactory results. What it should be expected in the future is the evaluation of these methods, not only in scientific environments dedicated to instrument development, but also in clinical chemistry laboratories, to evaluate their effectiveness and to give new and valid tools for TDM and for other qualitative or quantitative measurements of biomedical interest.