Similar to small-molecule drugs, there is also concern for protein-based therapeutics about their clinical use in patients with renal impairment including renal insufficiency and end-stage renal disease, which may modulate the efficacy and/or safety profile of these compounds. Theoretical considerations and clinical evidence suggest that the kidneys play a relevant role in the catabolism and thus elimination of only those protein therapeutics that have a size below the cutoff for glomerular filtration of approximately 60 kDa. Thus, the effect of renal impairment on protein therapeutics seems to be predictable and only relevant for compounds below this molecular weight cutoff. This is supported by clinical evidence that shows a lack of effect of renal impairment on large proteins such as monoclonal antibodies, whereas smaller proteins below the cutoff such as interleukin-10, growth hormone, erythropoietin, and anakinra experience a gradual decrease of their clearance and increase of their systemic exposure with increasing severity of renal impairment. Thus, dedicated renal impairment studies are warranted in the clinical development program of protein therapeutics that undergo glomerular filtration to establish the scientific rationale for their safe and efficacious use in patients with renal insufficiency.