There is no doubt regarding the therapeutic potential of nucleic acids (NA). However, to be functional NA require delivery into the cytoplasm or nucleus of the target cell. To overcome the extra-and intracellular barriers, NA are generally packaged into nanoparticles (i.e. nanomedicines). Unfortunately, current nanomedicines largely fail to deliver their NA cargo to its intracellular site of action. Interestingly, increasing evidence exists that major delivery hurdles can in part be overcome through helpful biological functions of low molecular weight compounds. This review summarizes how various (classes of) compounds can intervene at distinct stages of the NA delivery pathway. Small molecules are reported to influence processes including nanomedicine internalization, endosomal escape, intracellular trafficking and transgene expression. Of note, a number of compounds exert their effect by simultaneously affecting several of these steps. Interestingly, the low molecular weight adjuvants can be incorporated into the nanocarrier, conjugated to the nucleic acid or added before, during or after nanocarrier administration, indicating the versatility of this approach. (C) 2017 Elsevier Ltd. All rights reserved.