Isocyanides have diverse reactivity.
Isocyanides are stable to strong base (they are often made under strongly basic conditions), but they are sensitive to acid. In the presence of aqueous acid, isocyanides hydrolyse to the corresponding formamides:
This reaction is used to destroy odorous isocyanide mixtures. Some isocyanides can polymerize in the presence of Lewis and Bronsted acids.
Isocyanides participate in many multicomponent reactions of interest in organic synthesis, two of which are: the Ugi reaction and the Passerini reaction.
Isocyanides also participate in cycloaddition reactions, such as the [4+1] cycloaddition with tetrazines. Depending on the degree of substitution of the isocyanide, this reaction converts isocyanides into carbonyls or gives stable cycloadducts. They also undergo insertion into the C–Cl bonds of acyl chlorides in the Nef isocyanide reaction, a process that is believed to be concerted and illustrates their carbene character.
Isocyanides have also been shown to be a useful reagent in palladium catalysed reactions with a wide variety of compounds being formed using this method.
The α position of isocyanides have substantial acidity. For example, benzyl isocyanide has a pK of 27.4. In comparison, benzyl cyanide has a pK of 21.9. In the gas phase,  is 1.8 kcal/mol less acidic than .
Chlorination of isocyanides gives isocyanide dichlorides.