OBJECTIVE The branching behavior of vascular trees is often characterized using Murray's law. We investigate its validity using synthetic vascular trees generated under global optimization criteria. METHODS Our synthetic tree model does not incorporate Murray's law explicitly. Instead, we show that its validity depends on properties of the optimization model and investigate the effects of different physical constraints and optimization goals on the branching exponent that is now allowed to vary locally. In particular, we include variable blood viscosity due to the Fåhræus-Lindqvist effect and enforce an equal pressure drop between inflow and the micro-circulation. Using our global optimization framework, we generate vascular trees with over one million terminal vessels and compare them against a detailed corrosion cast of the portal venous tree of a human liver. RESULTS Murray's law is fulfilled when no additional constraints are enforced, indicating its validity in this setting. Variable blood viscosity or equal pressure drop lead to different optima but with the branching exponent inside the experimentally predicted range between 2.0 and 3.0. The validation against the corrosion cast shows good agreement from the portal vein down to the venules. CONCLUSIONS Not enforcing Murray's law increases the predictive capabilities of synthetic vascular trees, and in addition reduces the computational cost. CONCLUSIONS The ability to study optimal branching exponents across different scales can improve the functional assessment of organs.