Steroid hormones are known to freely partition into lipid bilayers. As a case study, we investigated the behavior of the steroid hormone cortisone in a model lipid bilayer. First, we looked at energy barriers involved in the partitioning of a single molecule into a bilayer using umbrella sampling molecular dynamics simulations. A rather wide well of -4.5 kcal/mol was observed in the interfacial region between the lipid headgroup and tailgroup. Next, using two unconstrained molecular dynamics simulations with cortisone initially positioned at distinct locations within a bilayer, we studied the preferred location and orientation of the molecule. Finally, we observed how cortisone molecules could spontaneously insert and localize in a bilayer from bulk solution. The three independent approaches produced a converged picture of how cortisone behaves in a model lipid bilayer.