Clear cell renal cell carcinoma (ccRCC) is a major cancer yet has long evaded extensive efforts to target it chemotherapeutically. Recent efforts to characterize its proteome and metabolome in a grade-defined manner has resulted in a global proteometabolomic reprogramming model yielding a number of potential drug targets, many of which are under the control of transcription factor and MYC proto-oncogene, bHLH transcription factor. Furthermore, through the use of conventional technologies such as immunohistochemistry, protein moonlighting, a phenomenon wherein a single protein performs more than one distinct biochemical or biophysical functions, is emerging as a second mode of operation for ccRCC metabolo-proteomic reprogramming. This renders the subcellular localization of the grade-defining biomarkers an additional layer of grade-defining ccRCC molecular signature, although its functional significance in ccRCC etiology is only beginning to emerge.