zVAD‐fmk is a widely used pan‐caspase inhibitor that blocks apoptosis but has undesirable side effects, including autophagy. In this issue, Needs et al. propose that zVAD‐fmk induces autophagy by inhibiting the N‐glycanase NGLY1 rather than caspases. NGLY1 is essential for the ERAD response and patients with inactivating mutations in NGLY1 present with neurodevelopmental defects and organ dysfunction. The ability of NGLY1 to inhibit basal levels of autophagy may contribute to this pathology. This study demonstrates possible crosstalk between protein turnover and autophagy while also underscoring the importance of specificity when using chemical tools to interrogate these pathways. Comment on https://doi.org/10.1111/febs.16345 zVAD‐fmk is a pan‐caspase inhibitor that blocks apoptosis and also induces autophagy in some contexts. Needs et al. propose that zVAD‐fmk induces autophagy by inhibiting the N‐glycanase NGLY1. A different pan‐caspase inhibitor, qVD‐OPh, with a more highly selective warhead, does not inhibit NGLY1. This report underscores the importance of specificity when using chemical inhibitors to interrogate apoptosis and autophagy pathways. Comment on https://doi.org/10.1111/febs.16345