We report the fabrication of reactive and degradable cross-linked polymer multilayers by the reactive/covalent layer-by-layer assembly of a non-degradable azlactone-functionalized polymer [poly(2-vinyl-4,4-dimethylazlactone), PVDMA] with hydrolytically or enzymatically degradable polyamine building blocks. Fabrication of multilayers using PVDMA and a hydrolytically degradable poly(beta-amino ester) (PBAE) containing primary amine side chains yielded multilayers (similar to 100 nm thick) that degraded over similar to 12 days in physiologically relevant media. Physicochemical characterization and studies on stable films fabricated using PVDMA and an analogous non-degradable poly(amidoamine) suggested that erosion occurred by chemical hydrolysis of backbone esters in the PBAE components of these assemblies. These degradable assemblies also contained residual amine-reactive azlactone functionality that could be used to impart new functionality to the coatings post-fabrication. Cross-linked multilayers fabricated using PVDMA and the enzymatically degradable polymer poly(l-lysine) were structurally stable for prolonged periods in physiological media, but degraded over similar to 24 h when the enzyme trypsin was added. Past studies demonstrate that multilayers fabricated using PVDMA and non-degradable polyamines [e.g., poly(ethylenimine)] enable the design and patterning of useful nano/biointerfaces and other materials that are structurally stable in physiological media. The introduction of degradable functionality into PVDMA-based multilayers creates opportunities to exploit the reactivity of azlactone groups for the design of reactive materials and functional coatings that degrade or erode in environments that are relevant in biomedical, biotechnological, and environmental contexts. This degradable building block strategy should be general; we anticipate that this approach can also be extended to the design of amine-reactive multilayers that degrade upon exposure to specific chemical triggers, selective enzymes, or contact with cells by judicious design of the degradable polyamine building blocks used to fabricate the coatings.