The localization of Bestraphin-2 (Best2) to the ciliary NPE and the reduced IOP in heterozygous and homozygous Best2 Knockout mice is indeed interesting, and supports Bakall et al.'s (607) conclusion that Best2 may be involved in aqueous humor formation. The ocular hypotensive responses to timolol and brinzolamide in mice, while statistically significant, are relatively small, perhaps due to the low starting IOP in these anesthetized animals (10-12 mmHg). This reader was unimpressed by the rather small differences in IOP responsiveness to the drugs between normal and Best2 Knockout mice, and therefore feels that one cannot say as much as the authors infer about the role of Best2 in the pathways affected by these drug doses. Further, the doses used are enormous for these tiny eyes, and indeed for these animals would constitute a significant systemic dose, with unknown effects on IOP by a plethora of potential mechanisms. The authors should be commended for identifying a gene/protein that may have a role in aqueous formation and therefore represent a potential IOP target, and leave it there for now, pending further studies.