The unclear effect of the ARMS2/HTRA1 genetic locus on AMD pathophysiology and the controversial therapeutic approach proposed to help patients (i.e. inhibition or overexpression of HTRA1) (Csaky et al., 2022; Merle et al., 2022; Pan et al., 2022; Williams et al., 2021) led us to investigate HTRA1 activity in retinal homeostasis and in response to AMD-relevant stressors. This evidence concerns the gene ARMS2 and age-related macular degeneration.