Purpose of Review <p>To review evidence supporting human umbilical cord mesenchymal stem cells (UC-MSC) as an innovative model system advancing obesity precision medicine.</p> Recent Findings <p>Obesity prevalence is increasing rapidly and exposures during fetal development can impact individual susceptibility to obesity. UC-MSCs exhibit heterogeneous phenotypes associated with maternal exposures and predictive of child cardiometabolic outcomes. This recent evidence supports UC-MSCs as a precision model serving three purposes: (1) as a mechanistic tool to interrogate biological underpinnings of obesity in human studies, (2) as a sensitive index of early life causes and determinants of obesity, and (3) as a marker and transducer of susceptibility, highlighting populations most at risk for future obesity.</p> Summary <p>Data from UC-MSCs emphasize nutrient sensing and lipid partitioning as phenotypes most relevant to neonatal and early childhood adiposity and implicate a role for these cell-autonomous features of mesodermal tissues in the biological underpinnings of obesity.</p>