Circadian rhythms of physiology and behaviour, the most obvious being the cycle of sleep and wakefulness, adapt organisms to the 24 hour world of day and night. They are evident in all major organs, have a pervasive influence upon health and well-being, and are underpinned by daily cycles of gene and protein expression local to particular tissues. This widespread molecular patterning is orchestrated by the principal circadian pacemaker of the suprachiasmatic nucleus (SCN) within the hypothalamus. The past decade has witnessed the decoding of the timekeeping mechanism of the SCN, revealing it to be a delayed negative feedback loop of transcriptional and post-translational elements. At its heart, the negative regulatory clock proteins Period (Per1, 2, 3) and Cryptochrome (Cry1, 2) are first synthesised at the start of circadian day, and they then enter the nucleus to suppress activation of their cognate genes by complexes containing the positive regulators Bmal1 and Clock. Over the course of circadian night, Per and Cry levels decline until the negative regulation is relieved and the expression cycle can start again, thus defining the next circadian day. Of critical importance is the discovery that this molecular pacemaker is expressed in many cell types and in almost all major organs. These local clocks drive the local gene expression rhythms that define circadian physiology, but they are in turn synchronised to the solar cycle and one to another, by systemic endocrine, autonomic and metabolic cues ultimately dependent upon the SCN. This presentation will review how factors that alter the stability of clock proteins determine the period of SCN and peripheral circadian pacemakers. For example, isoforms of the enzyme casein kinase 1 have a critical role in phosphorylating Per proteins and thereby destabilising them, promoting their ubiquitinylation and proteasomal degradation. In contrast, degradation of Cry proteins is dependent upon the E3 ubiquitin ligase factor Fbxl3. Mutations in CK1 and Fbxl3 can, respectively, accelerate and slow down the SCN pacemaker and accompanying behavioural rhythms in vivo. This presentation will also consider the role of neuropeptidergic signalling in maintaining synchrony between the clock neurons of the SCN and the contribution of cAMP-dependent signalling in sustaining and synchronising cellular transcriptional rhythms. Finally, the role of neuropeptidergic outputs from the SCN in maintaining behavioural and physiological rhythms will also be described.