The blood-brain barrier remains a major roadblock to the delivery of drugs to the brain. While in vitro and in vivo measurements of permeability are widely used to predict brain penetration, very little is known about the mechanisms of passive transport. Detailed insight into interactions between solutes and cell membranes could provide new insight into drug design and screening. Here, we perform unbiased atomistic MD simulations to visualize translocation of a library of 24 solutes across a lipid bilayer representative of brain microvascular endothelial cells. A temperature bias is used to achieve steady state of all solutes, including those with low permeability. Based on free-energy surface profiles, we show that the solutes can be classified into three groups that describe distinct mechanisms of transport across the bilayer. Simulations down to 310 K for solutes with fast permeability were used to justify the extrapolation of values at 310 K from higher temperatures. Comparison of permeabilities at 310 K to experimental values obtained from in vitro transwell measurements and in situ brain perfusion revealed that permeabilities obtained from simulations vary from close to the experimental values to more than 3 orders of magnitude faster. The magnitude of the difference was dependent on the group defined by free-energy surface profiles. Overall, these results show that MD simulations can provide new insight into the mechanistic details of brain penetration and provide a new approach for drug discovery.