Cellular rhythms are ubiquitous at all levels of biological organization and involve biochemical oscillations that modulate the concentration of key metabolic substrates and second messengers. Among these, rhythmic variations in the cytosolic free calcium concentration have been shown to arise spontaneously or after stimulation by hormones or neurotransmitters. In the developing cochlea, ATP-dependent calcium oscillations occur in non-sensory cells of the lesser epithelial ridge either as a consequence of intercellular calcium wave propagation or due to sustained ATP stimulation in the submicromolar range [1]. Spontaneous calcium oscillations in the lesser epithelial ridge are rarely observed in cochlear organotypic cultures at room temperature, but their frequency is drastically increased upon blockade of ectonucleotidases, a manipulation that highlights the tonic release of ATP from these cells [2]. On the contrary spontaneous calcium transients are always observed in the greater epithelial ridge, in a class of non-sensory cells (first described by Koelliker) which transiently populate the sensory epithelium from the spiral limbus to the inner hair cells. Spontaneous calcium transients in these cells have been attributed to release of ATP through connexin hemichannels [3, 4]. We recently demonstrated that cochlear non-sensory cells of the lesser and the greater epithelial ridge share the same PLC- and IP3R-dependent signal transduction cascade activated by ATP. Furthermore, we found that: (a) phosphatidylinositol phosphate kinase type 1γ is primarily responsible for the synthesis of the PIP2 pool in the cell syncytia that support auditory hair cells; (b) spatially graded impairment of this signalling pathway in cochlear non-sensory cells causes a selective alteration in the acquisition of hearing [5]. Previous studies had noted that ATP-dependent calcium oscillations in non-sensory cells of the cochlea feed-back on connexin expression and participate in the coordinated regulation of connexin 26 and connexin 30 through NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). We extended those findings demonstrating that connexin 26 and connexin 30 are both targets and effectors of calcium signalling in the developing cochlea. Altogether, these experiments have highlighted a crucial link in cochlear non-sensory cells between the expression and function of connexin 26 and connexin 30, ATP release, calcium waves, periodic calcium transients and NF-κB signalling networks, but other calcium-dependent transcription factors used by non-excitable cells may be involved. Clarifying the pathogenesis of sensorineural hearing loss and deafness due to connexin dysfunction (DFNB1, DFNA3; http://hereditaryhearingloss.org/) is just one aspect of the problem. The other critical issue is discovering appropriate treatments. Gene delivery with vectors derived from recombinant adeno-associated viruses has been successfully explored as a means to restore connexin expression and rescue intercellular coupling and calcium signalling in cochlear organotypic cultures from connexin-knockout mice with defective expression of connexin 26 and connexin 30 [6, 7]