Next-generation DNA sequencing technology has dramatically advanced clinical oncology through the identification of therapeutic targets and molecular biomarkers, leading to the personalization of cancer treatment with significantly improved outcomes for many common and rare tumor entities. More recent developments in advanced tumor profiling now enable dissection of tumor molecular architecture and the functional phenotype at cellular and subcellular resolution. Clinical translation of high-resolution tumor profiling and integration of multi-omics data into precision treatment, however, pose significant challenges at the level of prospective validation and clinical implementation. In this review, we summarize the latest advances in multi-omics tumor profiling, focusing on spatial genomics and chromatin organization, spatial transcriptomics and proteomics, liquid biopsy, and ex vivo modeling of drug response. We analyze the current stages of translational validation of these technologies and discuss future perspectives for their integration into precision treatment. Keywords: cancer biomarkers; ex vivo modeling; liquid biopsy; precision treatment; spatial multi-omics; tumor molecular profiling.