Hormone activated estrogen receptors (ERs) have long been appreciated as potent mediators of gene expression in female reproductive tissues. These highly targeted responses likely evolved from more elemental roles in lower organisms, in agreement with their widespread effects in the cardiovascular, immunological, central nervous, and skeletal tissue systems. Still, despite intense investigation, the multiple and often perplexing roles of ERs retain significant attention. In the skeleton, this in part derives from apparently opposing effects by ER agonists on bone growth versus bone remodeling, and in younger versus older individuals. The complexity associated with ER activation can also derive from their interactions with other hormone and growth factor systems, and their direct and indirect effects on gene expression. We propose that part of this complexity results from essential interactions between ERs and other transcription factors, each with their own biochemical and molecular intricacies. Solving some of the many questions that persist may help to achieve better, or better directed, use of agents that can drive ER activation in focused and possibly tissue restricted ways.