Formalin-fixation and paraffin-embedding (FFPE) is the standard preservation process of diagnostic tissue specimens in pathology institutes worldwide. FFPE provides excellent tissue architecture for histopathological evaluation and allows sample storage at low costs for decades. Optimization of sample preparation protocols rendered even low amounts of FFPE tissue (including endoscopic biopsies or punch biopsies) amenable to liquid chromatography - tandem mass spectrometry (LC-MS/MS). With millions of specimens being stored in pathology archives the value of FFPE tissue in proteomics-based identification of diagnostic, prognostic, and predictive biomarkers cannot be overestimated. Here, we present various diseases in which we use FFPE LC-MS/MS as a powerful tool in diagnostic molecular pathology either complementing or potentially replacing other techniques in routine pathology. Among these, amyloidosis subtyping may serve as a paramount example for which FFPE-LC-MS/MS can be considered as the diagnostic gold standard with better performance than the widely used immunohistochemical based approach. The term "amyloidosis" defines a disease, sharing the deposition of misfolded proteins in the interstitium of various tissues by formation of insoluble fibrils. These deposits damage the tissue structure and impair cell or organ function with varying severity and dynamics, depending on the amyloidosis subtype. Thus, the clinician relies on a precise amyloidosis subtyping for adequate patient care. Other examples in which we use FFPE-proteomics to support the clinical decision making are patients discussed in the molecular tumor or inflammation board (MTB/MiB) of the center for personalized medicine (ZPM). Here, FFPE proteomics also in combination with AI can clarify the diagnosis in borderline or unclear cases (e.g. Crohn"s disease vs. ulcerative colitis or cancer of unknown primary (CUP)). Furthermore, proteomic profiles may also reveal or confirm (as suggested by genomic or transcriptomic analyses) predictive biomarkers for individualized treatment decisions. Taken together, FFPE-LC-MS/MS has already entered the stage of advanced molecular pathology and will further exploit its full potential in precision diagnostics and personalized medicine.