In the functional proteome era, the proteomic profiling of clinicopathologic-annotated tissues is an essential step for mining and evaluating candidate biomarkers for disease. For many diseases, but especially cancer, the development of predictive biomarkers requires performing assays directly on the diseased tissue. The last decade has seen the explosion of both prognostic and predictive biomarkers in the research setting but few of these biomarkers have entered widespread clinical use. Previously, application of routine proteomic methodologies to clinical formalin-fixed and paraffin-embedded tissue specimens has provided unsatisfactory results. In this paper, we will discuss recent advancements in proteomic profiling technology for clinical applications. These approaches focus on the retention of histomorphologic information as an element of the proteomic analysis.