<p>Critical care has produced hundreds of neutral randomized trials, in part because therapies have been tested in biologically incoherent populations that dilute meaningful treatment effects. Syndromic diagnoses such as sepsis, acute respiratory distress syndrome, and traumatic brain injury group distinct pathobiological states under a single label, limiting the ability to detect treatment-responsive subgroups. While high-dimensional omics technologies have revealed this biologic heterogeneity, the field lacks a practical framework to translate these insights into clinical trial design and bedside decision-making. This Review addresses the translational gap in precision critical care through a pathway-level framework. We synthesize advances in genomics, transcriptomics, proteomics, and metabolomics, highlighting their roles in capturing susceptibility, host response, effector function, and real-time physiology. We propose pathway-focused biomarkers as clinically translatable signatures that preserve biological mechanisms while enabling practical measurement. We outline how pathway enrichment, network analysis, and multi-omic integration can identify these programs, and how feature selection can derive parsimonious biomarker panels for clinical use. This approach also supports pathway-guided drug repurposing by linking dysregulated molecular programs to existing therapies. Together, these signatures provide a framework for predictive enrichment, aligning patient selection with therapeutic mechanisms and facilitating implementation within adaptive platform trials. This Review serves as a practical primer that outlines the concepts and methods needed to translate omics into clinically actionable tools. By shifting from syndromic classification to pathway-defined biology, it provides a framework for biomarker development, trial design, and precision critical care.</p>