Targeted gene delivery relies on the ability to limit the expression of a transgene within a defined cell/tissue population. Exploiting genetic and phenotypic differences between cell types presents a window for targeted gene delivery. One genetic difference that may be exploited is differences in MicroRNA expression. MicroRNAs represent a class of highly powerful and effective regulators of gene expression that act by binding to a specific sequence present in the corresponding messenger RNA. Involved in almost every aspect of cellular function, many miRNAs have been discovered with expression patterns specific to developmental stage, lineage, cell-type, or disease stage. Exploiting the binding sites of these miRNAs allows for construction of targeted gene delivery platforms with a diverse range of applications. Here, we summarize our studies exploiting the differential expression of miRNA in cancerous verses healthy normal tissue to achieve targeted gene delivery. We will discuss the use of endogenous miR122 and miR199 to limit gene expression to hepatocellular carcinoma (liver cancer), pointing to the pros and cons of this approach. Additionally, we will discuss criteria that are important when choosing a particular miRNA for targeting and tips and tricks learnt when designing miRNA-regulated expression cassettes.