Non-protein-coding transcripts have been conserved throughout evolution, indicating that crucial functions exist for these RNAs. For example, microRNAs (miRNAs) have been found to modulate most cellular processes. The protein classes of RNA-binding proteins include essential regulators of miRNA biogenesis, turnover and activity. RNA-RNA and protein-RNA interactions are essential for post-transcriptional regulation in normal development and may be deregulated in disease. In reviewing emerging concepts of the interplay between miRNAs and RNA-binding proteins, we highlight the implications of these complex layers of regulation in cancer initiation and progression.