Vocal folds, housed in the upper respiratory tract, are important to daily breathing, speech and swallowing functions. Irreversible changes to the vocal fold mucosae, such as scarring and atrophy, require a regenerative medicine approach to promote a controlled regrowth of the extracellular matrix (ECM)-rich mucosa. Various biomaterial systems have been engineered with an emphasis on stimulating local vocal fold fibroblasts to produce new ECM. At the same time, it is imperative to limit the foreign body reaction and associated immune components that can hinder the integration of the biomaterial into the host tissue. Modern biomaterial designs have become increasingly focused on actively harnessing the immune system to accelerate and optimize the process of tissue regeneration. An array of physical and chemical biomaterial parameters have been reported to effectively modulate local immune cells, such as macrophages, to initiate tissue repair, stimulate ECM production, promote biomaterial-tissue integration, and restore the function of the vocal folds. In this perspective paper, the unique immunological profile of the vocal folds will first be reviewed. Key physical and chemical biomaterial properties relevant to immunomodulation will then be highlighted and discussed. A further examination of the physicochemical properties of recent vocal fold biomaterials will follow to generate deeper insights into corresponding immune-related outcomes. Lastly, a perspective will be offered on the opportunity of integrating material-led immunomodulatory strategies into future vocal fold tissue engineering therapies.