Macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor on myeloid cells that represents a promising target for Th1-stimulating adjuvants. We report on the synthesis of branched and aromatic glucose monoesters and glycosides and their activation of mouse and human Mincle. In studies using mMincle, derivatives containing aromatic groups in the 6-O-acyl chain were poor Mincle agonists, while analogues with branched lipophilic groups at the glucose 6-position and anomeric hydroxy or methoxy groups exhibited better Mincle-mediated agonist activity than compounds with a docosyl group at the anomeric position. In contrast, all derivatives, except those containing the aromatic groups on the 6'-acyl chain, were able to signal via hMincle, with different compounds exhibiting different requirements for the EPN motif in the carbohydrate recognition domain (CRD) of hMincle for signaling. Functional assays using human monocytes revealed that docosyl α-glucopyranoside leads to significantly higher levels of IL-1β and IL-8 production by monocytes compared to those elicited by trehalose dibehenate (TDB). The facile two-step synthesis of docosyl α-glycoside in 75% overall yield makes it a particularly attractive target for adjuvant research.