The functions of macrophages in the innate immune system require the constitutive expression of a wide range of myeloid-specific genes, including various pattern recognition receptors, as well as the inducible expression of a suite of genes required to initiate inflammation and eliminate pathogens. Our overall aim is to understand the transcriptional networks that underlie both macrophage-specific transcription and the response to pathogen components such as lipopolysaccharide (LPS). The approaches used include detailed functional analysis of specific promoters, such as that of the CSF1 receptor, global cDNA microarray expression profiling, high throughput real-time PCR analysis of all the transcription factors encoded by the mammalian genome, full length cDNA library construction and sequencing, CAGE analysis to identify specific promoters used in macrophages and motif analysis to detect candidate cis-acting elements in co-regulated genes in macrophages. This review discusses some of the progress in moving towards a transcriptional network model for mouse macrophage activation by LPS, as well as insight into the role of alternative promoter usage and polyadenylation in generating functional protein variants that impact on signalling in macrophages.