The fact that nucleic acid bases recognize each other to form pairs is a canonical part of the dogma of biology. However, they do not recognize each other well enough in water to account for the selectivity and efficiency that is needed in the transmission of biological information through a cell. Thus proteins assist in this recognition in multiple ways, and recent data suggest that these mechanisms of recognition can vary widely with context. To probe how the chemical differences of the four nucleobases are defined in various biological contexts, chemists and biochemists have developed modified versions that differ in their polarity, shape, size, and functional groups. This brief review covers recent advances in this field of research.