The evaluation of biopsied solid organ tissue has long relied on visual examination using a microscope. Immunohistochemistry is critical in this process, labeling and detecting cell lineage markers and therapeutic targets. However, while the practice of immunohistochemistry has reshaped diagnostic pathology and facilitated improvements in cancer treatment, it has also been subject to pervasive challenges with respect to standardization and reproducibility. Efforts are ongoing to improve immunohistochemistry, but for some applications, the benefit of such initiatives could be impeded by its reliance on monospecific antibody-protein reagents and limited multiplexing capacity. This perspective surveys the relevant challenges facing traditional immunohistochemistry and describes how mass spectrometry, particularly liquid chromatography-tandem mass spectrometry, could help alleviate problems. In particular, targeted mass spectrometry assays could facilitate measurements of individual proteins or analyte panels, using internal standards for more robust quantification and improved interlaboratory reproducibility. Meanwhile, untargeted mass spectrometry, showcased to date clinically in the form of amyloid typing, is inherently multiplexed, facilitating the detection and crude quantification of 100s to 1000s of proteins in a single analysis. Further, data-independent acquisition has yet to be applied in clinical practice, but offers particular strengths that could appeal to clinical users. Finally, we discuss the guidance that is needed to facilitate broader utilization in clinical environments and achieve standardization. Display omitted •Immunohistochemistry workflows are poorly standardized.•Mass spectrometry may complement existing tests for proteins in solid tissues.•Targeted workflows could help clarify borderline immunohistochemistry cases.•Untargeted assays provide relative quantification of 100s to 1000s of proteins.•Guidance is needed to help clinical labs develop robust tools for solid tissues. For many years, immunohistochemistry has been the primary tool in pathology for protein localization and quantification in solid tissues, but it is poorly standardized and suffers from practical limitations. The field is ripe for novel complementary technologies to help with diagnosis. This perspective focuses on the issues hampering immunohistochemistry and highlights how liquid chromatography-tandem mass spectrometry in particular is well-positioned to complement existing testing. We also discuss where guidance is needed to ensure rigor in clinical environments.