This chapter covers advances in the functionalization of purine and pyrimidine nucleosides by direct C-H bond activation. Although the review mainly focuses on strategies developed for direct functionalization of C-H bonds within the frame of purine and pyrimidine rings, it also covers methods for N1 purinyl-directed ortho functionalization of 6-N-substituted adenine and 6-substituted purine nucleosides. Strategies for functionalization have been divided into a few major categories based on the (i) position of functionalization (e.g., C-8 vs C-6 vs C2 in purines or C-6 vs C-5 in pyrimidines), and (ii) type of substrates which are coupled to nucleobases (e.g., aryl- or alkenyl halides, alkenes or amines). The scope and efficiency of these coupling reactions, along with some mechanistic considerations, are discussed.