Cancer is now being viewed not as a single genetic disease but as a multi-layered, multi-level disease that exists on a systems level and is a biochemical process that is powered by dynamic, multi-layered interactions with molecules. This review will take the systems biology approach by combining metabolomics, proteomics, and epigenomics to explain the biochemical heterogeneity and adaptive plasticity of cancer. The bioenergetic requirements of growing tumor cells are manifested through metabolomic reprogramming which is the altered glycolysis, lipid metabolism, and redox balance. Simultaneously, proteomic changes remodel signaling pathways, which mediate cell survival, immune resistance, and treatment resistance. Additional epigenomic changes such as DNA methylation, changes in histone positioning and regulation of non-coding RNAs also coordinate the pattern of gene expression without changing the sequence of the DNA itself. The intersection of these layers of omics points to cancer as an outcome of interdependent biochemical processes, and not single events at the molecular level. Recent developments in the field of multi-omics integration, which has been made possible by the high-throughput and computational modeling technologies, have allowed the discovery of new biomarkers and therapeutic targets with greater specificity and predictive capability. Notably, this integrative model changes the existing paradigm of reductionist approaches to the holistic tumor biology concept. This review identifies the opportunity of systems-level knowledge in informing precision oncology by mapping cross-talk between metabolic pathways, protein networks, and epigenetic landscapes. Finally, the combination of multi-omics information offers a strong foundation to unlock the complexity of tumors, enhance the early diagnosis of cancer, and inform the design of tailored therapeutic approaches during cancer treatment.