Trimethyl orthoformate is a useful building block for creating methoxymethylene groups and heterocyclic ring systems. It introduces a formyl group to a nucleophilic substrate, e.g. RNH to form R-NH-CHO, which can undergo further reactions. It is used in the production of the fungicides, azoxystrobin, and picoxystrobin, as well as for some members of the floxacin family of antibacterial drugs. 
A number of pharmaceutical intermediates are also made from trimethyl orthoformate.
Trimethyl orthoformate is also an effective reagent for converting compatible carboxylic acids to their corresponding methyl esters. Alternatively, acid-catalyzed esterifications with methanol can be driven closer to completion by employing trimethyl orthoformate to convert water byproduct to methanol and methyl formate.