While proteomics technologies have improved substantially over the last several years, the improvements are often overshadowed by the paradigm shift that has occurred in genomics. These new genomics technologies have enabled genetic and functional genomics experiments on a scale and detail not previously imaginable. Yet the success of these pioneering experiments does not diminish the enormity of the problems that lie ahead. The ultimate question being, how does the information stored in a genome encode a complex multicellular organism? While the large-scale sequencing of nucleic acids is relatively robust, this information cannot be fully understood without studying the proteins – the main functional macromolecules encoded by the genome. Unfortunately, proteomic technologies are not as routine or robust as their genomics equivalent, and the challenges associated with comprehensive measurement of the entire protein complement of a cell or tissue is more demanding. I will present efforts within our laboratory to improve the reproducibility, throughput, and comprehensiveness of proteomics while also attempting to reduce the cost. Progress and current challenges will be presented.