<p>Heterogeneity between critically ill patients with sepsis is a major barrier to the discovery of effective therapies. The use of machine learning techniques, coupled with improved understanding of sepsis biology, has led to the identification of patient subphenotypes. This exciting development may help overcome the problem of patient heterogeneity and lead to the identification of patient subgroups with treatable traits. Re-analyses of completed clinical trials have demonstrated that patients with different subphenotypes may respond differently to treatments. This suggests that future clinical trials that take a precision medicine approach will have a higher likelihood of identifying effective therapeutics for patients based on their subphenotype. In this review, we describe the emerging subphenotypes identified in the critically ill and outline the promising immune modulation therapies which could have a beneficial treatment effect within some of these subphenotypes. Furthermore, we will also highlight how bringing subphenotype identification to the bedside could enable a new generation of precision-medicine clinical trials.</p>