Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification of clinically relevant biomarkers, and which patients might benefit most. Clinical trials of iron- and ferroptosis-targeted therapies are beginning to provide some answers, but there is growing interest in developing new ferroptosis inhibitors. We describe newly identified ferroptosis targets, opportunities, and challenges in NDD, as well as key considerations for progressing new therapeutics to the clinic.