We have examined mechanisms of antigen uptake by dendritic cells (DC). While multiple experimental approaches have been used, live cell imaging has been especially informative, and is reviewed here. DC were shown to bind to and internalize bacteria, but not inert particles, demonstrating an unexpected selectivity that included sensing of secreted bacterial products and subsequent cell activation. This led to the observation that induced calcium fluxes in these cells could be propagated to other cells via thin membrane connections termed tunneling nanotubules that were shown to form an extensive network between cells, and are also present in other cell types. These data are discussed in terms of DC function, and also demonstrate the power of live cell imaging in elucidating complex biological phenomena that are not readily revealed using static imaging approaches or by biochemical analyses.