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RORyt/y driven type-17 “pro-inflammatory “gene expression profile has been implicated in the pathogenesis of several human immune-mediated diseases and remains a compelling target for therapeutic intervention. However, several challenges, from both drug discovery and biology standpoint, have made it intractable. While biologics targeting IL-23, IL-17, IL-17R, and other cytokines in the ROR pathway have demonstrated clinical efficacy in psoriasis, ankylosing spondylitis, etc., it has been challenging to extend the utility of these therapeutics beyond a handful of autoimmune diseases, especially in atopic or rheumatic diseases. This review summarizes the complexities in defining the pathogenicity of the human type-17 pathway and underscores the need for targeting a phenotypically heterogeneous and therapeutically relevant pathogenic cell subset marked by CD161.