AbstractHereditary degeneration of photoreceptors has been linked to over-activation of Ca²⁺-permeable channels, excessive Ca²⁺-influx, and downstream activation of Ca²⁺-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca²⁺-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca²⁺-influx, most probably by blocking the pore of Ca²⁺-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca²⁺ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca²⁺-independent degenerative mechanisms.