The Capped Analysis of Gene Expression (CAGE) recently provided a comprehensive survey of the start sites of mammalian mRNAs, lncRNAs, pri-miRNAs and enhancer RNAs; in turn marking gene proximal promoters and the active enhancer landscape across an atlas of primary human cell and tissue types. Here, I describe the widespread use of alternate start sites in primary human monocytes, and discuss the functional consequences of alternate transcription start sites on the monocyte maturation and activation. These findings provide insights into the first molecular changes that monocytes undergo on engagement with a variety of fungal, mycobacterial and bacterial pathogens.