Research into novel therapeutic strategies for recalcitrant chronic rhinosinusitis (rCRS) has grown in the last few years. The biggest breakthrough came with monoclonal antibodies targeting type 2 inflammation (i.e., dupilumab, mepolizumab, and omalizumab), which have shown efficacy for treating CRS with nasal polyps (CRSwNP) in large phase three clinical trials [1–3], followed by several real-life publications indicating efficacy from around the globe [3–6]. With multiple trials currently ongoing for other CRS subtypes such as allergic fungal rhinosinusitis (AFRS) [7] and CRSsNP [8], the use of biologics is likely to significantly change the landscape of CRS management and is destined to increase with time. However, not every patient is a candidate for these medications. In our experience, individuals whose symptoms are primarily due to recalcitrant biofilm formation are unlikely to improve with monoclonal antibodies. Similarly, patients who don’t have typical signs of type 2 inflammation, such as elevated tissue or peripheral eosinophils, eosinophilic mucin, or high IgE levels, may have a poor response to these drugs. Consequently, there is still a need for other types of therapeutic strategies that can improve the health of rCRS patients, particularly those that are unlikely to benefit from, or unable to utilize, monoclonals that target type 2 inflammation.