Altered metabolism is associated with many human diseases. Human genome-scale metabolic models (GEMs) were reconstructed within systems biology to study the biochemistry occurring in human cells. However, the complexity of these networks hinders a consistent and concise physiological representation. We present here redHUMAN, a workflow for reconstructing reduced models that focus on parts of the metabolism relevant to a specific physiology using the recently established methods redGEM and lumpGEM. The reductions include the thermodynamic properties of compounds and reactions guaranteeing the consistency of predictions with the bioenergetics of the cell. We introduce a method (redGEMX) to incorporate the pathways used by cells to adapt to the medium. We provide the thermodynamic curation of the human GEMs Recon2 and Recon3D and we apply the redHUMAN workflow to derive leukemia-specific reduced models. The reduced models are powerful platforms for studying metabolic differences between phenotypes, such as diseased and healthy cells. The complexity of genome-scale metabolic networks (GEMs) hinders their application in specific physiological contexts. Here, the authors introduce a framework to reduce thermodynamically curated GEMs to the subnetworks of interest and demonstrate its application by deriving leukemia-specific models.