This　perspective　focuses　on　illustrating　the　underappreciated　connections　between　reactive　carbonyl　species　(RCS),　initial　binding　in　the　nonenzymatic　glycation　(NEG)　process,　and　nonenzymatic　covalent　protein　modification　(here　termed　NECPM).　While　glucose　is　the　central　species　involved　in　NEG,　recent　studies　indicate　that　the　initially-bound　glucose　species　in　the　NEG　of　human　hemoglobin　(HbA)　and　human　serum　albumin　(HSA)　are　non-RCS　ring-closed　isomers.　The　ring-opened　glucose,　an　RCS　structure　that　reacts　in　the　NEG　process,　is　most　likely　generated　from　previously-bound　ring-closed　isomers　undergoing　concerted　acid/base　reactions　while　bound　to　protein.　The　generation　of　the　glucose　RCS　can　involve　concomitantly-bound　physiological　species　(e.g.,　inorganic　phosphate,　water,　etc.);　here　termed　effector　reagents.　Extant　NEG　schemes　do　not　account　for　these　recent　findings.　In　addition,　effector　reagent　reactions　with　glucose　in　the　serum　and　erythrocyte　cytosol　can　generate　RCS　(e.　g.,　glyoxal,　glyceraldehyde,　etc.).　Recent　research　has　shown　that　these　RCS　covalently　modify　proteins　in　vivo　via　NECPM　mechanisms.　A　general　scheme　that　reflects　both　the　reagent　and　mechanistic　diversity　that　can　lead　to　NEG　and　NECPM　is　presented　here.　A　perspective　that　accounts　for　the　relationships　between　RCS,　NEG,　and　NECPM　can　facilitate　the　understanding　of　site　selectivity,　may　help　explain　overall　glycation　rates,　and　may　have　implications　for　the　clinical　assessment/control　of　diabetes　mellitus.　In　view　of　this　perspective,　concentrations　of　ribose,　fructose,　Pi,　bicarbonate,　counter　ions,　and　the　resulting　RCS　generated　within　intracellular　and　extracellular　compartments　may　be　of　importance　and　of　clinical　relevance.　Future　research　is　also　proposed.