The explosion of new functional genomic technologies has revolutionised our approach to systems biology and highlighted a number of novel targets in neurodegenerative and, to a lesser extent, psychiatric diseases. However, the exact structure of a protein, its sub-cellular location, and post-translation modifications are critical to defining its function. Traditionally these properties have been defined through focused characterization of a single protein or protein complex. Mass-spectrometry proteomics enables high-throughput profiling of the larger proteome, but is often applied to bulk tissue, with quantification summarised to the level of protein groups. Here I will argue that this level of analysis inadequately captures the complexity of protein abundance in the human brain, and will talk about my experience developing methods to improve the resolution of proteomic techniques. I will describe analytical approaches to quantification of protein isoforms via the integration of high-throughput transcriptomics and proteomics, and the use of biochemical methods for the sub-cellular localisation of proteins in post-mortem human tissue.