Access to the brain is restricted by the low permeability of the blood-brain barrier (BBB), greatly hampering modern drug delivery efforts. A promising approach to overcome this boundary is to utilize biomacromolecules (peptides, nucleic acids, carbohydrates) as targeting ligands on nanoscale delivery vehicles to shuttle cargo across the BBB. In this mini-review, we highlight the most recent approaches for crossing the BBB using synthetic nanoscale constructs decorated with members of these general classes of biomacromolecules to safely and selectively deliver therapeutic materials to the brain. This mini-review highlights the most recent advances in the design and application of synthetic nanoscale constructs that utilize biomacromolecular ligands (peptides, nucleic acids, carbohydrates) to target and cross the blood-brain barrier (BBB).