Over the last 15 years, proteomics has evolved into a major field of biomedical/biological research, but one that is still well short of achieving its vast potential. Arising as a true paradigm shift from protein chemistry, it is rooted in the determination of the human genome sequence (and a rapidly growing number of additional genome sequences) and three principal technological advances – 2D gels, protein and nucleic acid arrays and MALDI/ESI mass spectrometry. It has, as its generalized objective, the complete description of individual proteomes - derived from whole organisms to biologically defined subsets - and requires the identification/description of the structure/function of all proteins in the set including, where present, splice variants and post-translational modifications. It also requires the determination of the both the stable and transient protein-protein interactions that make up the highly complex cellular networks of even the simplest organisms. Achieving these objectives have been generally driven by large scale, ‘shotgun’ experiments. However, more recently the correlation with other ‘omic data (genomic, transcriptomic and metabolomic), important for systems biology experimentation, has emerged as a major objective and have emphasized the necessity of quantitative data. This has lead to the emergence of SRM/MRM/PRM-based methodology and the measurement of individual entities/modifications under normal and pathological conditions as an increasingly popular approach. While there have been notable advances in both types of efforts, providing some useful new insights, progress has been slow, particularly in translational applications, relative to the scope of what remains to be done. An overview of the accomplishments (both positive and negative) of the past decade and half, and some predictions about what the next decade and a half will bring, will be presented.