Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.