The protein function as well as its stability is governed by the amino
acid sequence which in turn defines the collective noncovalent intera
ctions leading to its specific conformation. Hence, it is not surprisi
ng that chemical modification with monofunctional and bifunctional rea
gents (the latter is called chemical crosslinking) causes structural c
hanges (sometimes even subtle) which can result in significant changes
in the stability. This review, while recapitulating the early lessons
, analyses recent work (including work from authors' laboratory) invol
ving these twin approaches for protein stabilization. In the case of c
hemical modification, both surface hydrophilization and enhancing surf
ace hydrophobicity are reported to have enhanced protein stability in
different cases. For cross-linking, the nature, span, and position of
the cross-link are important factors in the stabilization achieved. It
is also pointed out that in the case of aqueous-organic cosolvent mix
tures, protein stability may depend upon the nature of the organic sol
vents. In the case of polyphenol oxidase and trypsin (at least), it is
possible to choose ''good'' solvents on the basis of the polarity ind
ex of the solvent.