Circulating monocytes can infiltrate mucosal or inflamed tissues where they differentiate into either macrophages or dendritic cells. This paradigm is supported by numerous studies conducted in mice and in different in vitro settings for human cells. Determining whether it holds true in vivo in humans is essential for the successful design of monocyte-targeting therapies. Despite limitations inherent to working with human samples, there is accumulating evidence of the existence of in vivo-generated monocyte-derived cells in humans. Here, we review recent studies showing the recruitment of human monocytes into tissues and their differentiation into macrophages or dendritic cells, in normal or pathological settings. We examine the methods available in human studies to demonstrate the monocytic origin of infiltrating cells. Finally, we review the functions of human monocyte-derived cells and how they might contribute to pathogeny.