DNA-mediated self-assembly of colloids has emerged as a powerful tool to assemble the materials of prescribed structure and properties. The uniqueness of the approach lies in the sequence-specific, thermo-reversible hybridization of the DNA-strands based on Watson–Crick base pairing. Grafting particles with DNA strands, thus, results into building blocks that are fully programmable, and can, in principle, be assembled into any desired structure. There are, however, impediments that hinder the DNA-grafted particles from realizing their full potential, as building blocks, for programmable self-assembly. In this short review, we focus on these challenges and highlight the research around tackling these challenges.