Many of you, especially those working with more exotic techniques have likely experienced the following: When you explain your technique to someone else, they almost always end up either solidly in the optimistic “Wow, this technique can measure everything!” or in the pessimistic “Can this technique measure anything at all?” camp, but seldomly anywhere between. That certainly has been my experience with atomic force microscopy induced resonance (AFM-IR). By combining a scanning probe tip as transducer with a pulsed, tunable mid-infrared (mid-IR) laser, this technique is able to provide molecular chemical images at 20 nm spatial resolution. This capability makes AFM-IR an exciting tool for chemical characterization across many fields. We can use it to visualize phases withing polymeric materials and chemically identify them [1], [2], perform chemical analysis of individual nanoscale vesicles [3] and measure the distribution of cell components[4], to mention a few. However, even after a decade working with AFM-IR, I often find myself oscillating rapidly between the above mentioned optimistic and pessimistic camp when it comes to AFM-IRs capabilities: “Yesterday, I took an AFM-IR spectrum of a single molecule and today it isn’t even able to find several percent of my analyte in this micron sized sample? Why?” There is – of course – an answer to this question. Like with any photothermal spectroscopic measurement, there are mechanical, thermal and optical contributions to the signal. In our work, we’ve started to unravel to be able to understand and predict which AFM-IR configurations and imaging modes work well for a particular analytical task, for a particular sample. Acknowledgements GR acknowledges financial by the European Union’s Horizon 2020 research and innovation programme under grants agreements No. 861985 (PeroCUBE) and No 953234 (TUMOR-LN-oC), and COMET Centre CHASE, funded within the COMET − Competence Centers for Excellent Technologies programme by the BMK, the BMDW and the Federal Provinces of Upper Austria and Vienna. The COMET programme is managed by the Austrian Research Promotion Agency (FFG). ACvDS acknowledges financial support by COMET Centre CHASE, UY acknowledges financial support by PeroCUBE, EH and NH acknowledge financial support by TUMOR-LN-OC. YZ acknowledges financial support by European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement No 860808. References [1] A. C. V. D. dos Santos, B. Lendl, and G. Ramer, “Systematic analysis and nanoscale chemical imaging of polymers using photothermal-induced resonance (AFM-IR) infrared spectroscopy,” Polym. Test., vol. 106, p. 107443, Feb. 2022, doi: 10.1016/j.polymertesting.2021.107443. [2] A. C. V. D. dos Santos, D. Tranchida, B. Lendl, and G. Ramer, “Nanoscale chemical characterization of a post-consumer recycled polyolefin blend using tapping mode AFM-IR,” The Analyst, vol. 147, no. 16, pp. 3741–3747, 2022, doi: 10.1039/D2AN00823H. [3] K. Wieland, G. Ramer, V. U. Weiss, G. Allmaier, B. Lendl, and A. Centrone, “Nanoscale chemical imaging of individual chemotherapeutic cytarabine-loaded liposomal nanocarriers,” Nano Res., Sep. 2018, doi: 10.1007/s12274-018-2202-x. [4] A. C. V. D. dos Santos et al., “Nanoscale Infrared Spectroscopy and Chemometrics Enable Detection of Intracellular Protein Distribution,” Anal. Chem., Dec. 2020, doi: 10.1021/acs.analchem.0c02228.