Molecular observations reveal substantial biogeographic patterns of cyanobacteria within systems of connected lakes. An important question is the relative role of environmental selection and neutral processes in the biogeography of these systems. Here we quantify the effect of genetic drift and dispersal limitation by simulating individual cyanobacteria cells using an agent-based model (ABM). In the model, cells grow (divide), die and migrate between lakes. Each cell has a full genome that is subject to neutral mutation (i.e. the growth rate is independent of the genome). The model is verified by simulating simplified lake systems, for which theoretical solutions are available. Then, it is used to simulate the biogeography of the cyanobacterium Microcystis aeruginosa in a number of real systems, including the Great Lakes, Klamath River, Yahara River and Chattahoochee River. Model output is analyzed using standard bioinformatics tools (BLAST, MAFFT). The emergent patterns of nucleotide divergence between lakes are dynamic, including gradual increases due to accumulation of mutations and abrupt changes due to population takeovers by migrant cells (coalescence events). The model predicted nucleotide divergence is heterogeneous within systems and for weakly connected lakes it can be substantial. For example, Lakes Superior and Michigan are predicted to have an average genomic nucleotide divergence of 8,200 bp or 0.14%. The divergence between more strongly connected lakes is much lower. Our results provide a quantitative baseline for future biogeography studies. They show that dispersal limitation can be an important factor in microbe biogeography, which is contrary to the common belief, and could affect how a system responds to environmental change.iii ACKNOWLEDGMENTSWe thank Steve Chapra for providing the Great Lakes model and Euan Reavie for cyanobacteria concentration data in the Great Lakes. Peter Furth and Haris Koutsopoulos provided advice on the theoretical aspect. Haiwei Luo helped with the mutation rates. Three anonymous reviewers provided constructive criticism.