Renal cell cancer is among the most common forms of cancer in humans, with around 35,000 deaths attributed to kidney carcinoma in the European Union (EU) in 2012 alone. Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and the most lethal of all genitourinary cancers. Here we apply omics technologies to archival core biopsies to investigate the biology underlying ccRCC. Knowledge of these underlying processes should be useful for the discovery and/or confirmation of novel therapeutic approaches and ccRCC biomarker development. From partial or full nephrectomies of 11 patients, paired core biopsies of ccRCC affected tissue and adjacent non-tumorous tissue were both sampled and subjected to proteomics analyses. We combined proteomics results with our published mRNA-seq from the same patients and with published miRNA-seq data from an overlapping patient cohort from our institution. Statistical analysis and pathway analysis were performed with JMP Genomics (SAS) and Ingenuity Pathway Analysis (IPA, Qiagen), respectively. Proteomics analysis confirmed the involvement of metabolism and oxidative stress-related pathways in ccRCC, while the most affected pathways in the mRNA-seq data were related to the immune system. Unlike proteomics or mRNA-seq alone, a combinatorial cross-omics pathway analysis approach captured a broad spectrum of biological processes underlying ccRCC, such as mitochondrial damage, repression of apoptosis, and immune system pathways. Sirtuins, immunoproteasome genes and CD74 are proposed as potential targets for the treatment of ccRCC.