Hearing loss is the most common form of congenital birth defect, affecting an estimated 35 million children worldwide. To date, nearly 100 genes have been identified which contribute to a deafness phenotype in humans, however, many cases remain in which a causative mutation has yet to be found. In addition, the exact mechanism by which hearing loss occurs in the presence of many of these mutations is still not understood. This is due, in part, to the complex nature of the development and function of the cochlear duct, the organ of hearing. The cochlea undergoes an intricate morphogenetic development and requires the proper specification and maintenance of dozens of different cell types in order to function correctly. In the mature duct, an interplay between mechanotransducing sensory hair cells, supporting pillar and Dieters' cells, and generation of electrochemical potential by the stria vascularis are necessary to respond to sound stimuli. We utilized exome and RNA-sequencing experiments combined with mouse genetics in order to discover novel genes that play roles in cochlear development and function. Exome sequencing of families with profound hearing loss uncovered mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1), a critical regulator of alternative mRNA splicing. Analysis of Esrp1 mutant mice revealed a shortened cochlear duct, delay in hair cell differentiation and maturation, and loss of the stria vascularis due to inappropriate Fgf ligand usage, stemming from an alternatively spliced receptor, in these cells. To identify additional regulators of inner ear development we performed an RNA-seq experiment comparing the gene expression profiles of control and Smoecko otic vesicles, which lack a cochlear duct. This generated a dataset of hundreds of cochlear enriched transcripts including Growth Arrest Specific 2 (Gas2) a cytoskeletal binding protein with the potential to act as a regulator of cochlear development. We generated a Gas2 null mouse line and discovered that these animals have severe hearing impairment likely due to defects in microtubule organization in the pillar cells. Taken together, these studies implicate Esrp1 and Gas2 as novel hearing loss genes that regulate aspects of cochlear development and function.