Life in single cells is dictated by chance: reactions that involve small numbers of molecules generate spontaneous fluctuations that then enslave all dependent processes. Such ‘noise’ can randomize developmental pathways, disrupt cell cycle control or force metabolites away from their optimal levels. It can also be exploited when heterogeneity is advantageous, or even to obtain more reliable and deterministic control. The goal of the laboratory is to identify and understand the guiding principles behind these different phenomena. To this end we derive mathematical methods to interpret fluctuations, develop experimental methods to count molecules in single cells, and combine the two to study the simplest natural and engineered networks. Different applications may use different organisms, but E. coli is the first choice.