For many decades, the wedding of quantitative data with mathematical modeling has been fruitful, leading to important biological insights. Here, we review some of the ongoing efforts to gain insights into problems in microbiology – and, in particular, cell-cycle progression and its regulation – through observation and quantitative analysis of the natural fluctuations in the system. We first illustrate this idea by reviewing a classic example in microbiology – the Luria–Delbrück experiment – and discussing how, in that case, useful information was obtained by looking beyond the mean outcome of the experiment, but instead paying attention to the variability between replicates of the experiment. We then switch gears to the contemporary problem of cell cycle progression and discuss in more detail how insights into cell size regulation and, when relevant, coupling between the cell cycle and the circadian clock, can be gained by studying the natural fluctuations in the system and their statistical properties. We end with a more general discussion of how (in this context) the correct level of phenomenological model should be chosen, as well as some of the pitfalls associated with this type of analysis. Throughout this review the emphasis is not on providing details of the experimental setups or technical details of the models used, but rather, in fleshing out the conceptual structure of this particular approach to the problem. For this reason, we choose to illustrate the framework on a rather broad range of problems, and on organisms from all domains of life, to emphasize the commonality of the ideas and analysis used (as well as their differences).