Sepsis and septic shock exhibit a broad spectrum of immunological disorders with a very heterogeneous clinical manifestation. The heterogeneity makes understanding of pathomechanisms extremely difficult. With an aim to improve the outcome, this study employed clinico-transcriptomics approaches that effectively combine clinical and transcriptomics information to derive reproducible observations. The first clinico-transcriptomics approach was built to identify a subset ofpatients that might benefit from hydrocortisone (HC) treatment in septic shock patients. Serum ratio of IFNγ and IL-10 was found to be the best marker to make this treatment decision. It was validated further on three independent datasets. High ratio indicated better survival without HC treatment while a benefit was observed for low ratio when HC treatment was initiated. Transcriptomic evidence suggested that the patients with high ratio might be immunologicallyfit due to the presence of greater extent of activated macrophages and T-cells. The second clinico-transcriptomics approach was developed to reveal sex-based pathomechanisms in the trauma patients. The findings were validated in another dataset of patients with burn injuries. The approach included the synchronization of the time lapse of the profiles based on the temporal severity score of each patient. Females showed a better transcriptomic response in the mechanisms involving innate immunity, adaptive immunity, bio-energetic tolerance and wound healing. Sex-hormone receptor modulation in males by the treatment of Atraric acid and Flutamide have been shown to improve outcome in animal septic models. The transcriptomic evidence gathered in this thesis argued that such modulation might have enhanced the tolerance in the septic male mice. The insights provided by the clinico-transcriptomics approaches may significantly contribute to improving the outcome in critically ill patients with cortico- and sex- steroids.