Phytochromes are biliprotein light sensors that enable photosynthetic organisms to adapt to positive and negative light environments. The recent discovery of phytochromes in nonphotosynthetic bacteria and fungi document that phytochrome ancestors and their ancient signaling partners have evolved into components of signaling systems found in higher eukaryotes. These studies seek to define how tetrapyrrole and light signals are perceived by and propagated within the phytochrome molecule and transduced to downstream target molecules, specifically addressing the hypothesis that phytochromes function as sensors of linear tetrapyrrole (bilins) and light via regulation of their intrinsic protein kinase activities. Ubiquitous to aerobic organisms, bilins appear to play important signaling roles in metazoans, their levels being linked to anoxia, xenobiotic-induced oxidative stress and vascular damage. The mechanism of this ancient signaling pathway is therefore of fundamental importance for understanding and regulating analogous signaling systems in other eukaryotes, including humans. In addition to leading to new approaches to regulate light responsiveness and productivity of plants, our primary food source, another long term consequence of these studies is the development of phytochrome-based approaches for new light-based therapies. The long term goal is to define the structural basis for the regulatory functions of each member of the extended phytochrome family at the molecular level. This understanding will not only enable the design of new approaches for regulation of light-mediated growth and development of agronomically important crop species, but will facilitate development of phytochrome-based technologies for regulation of important biochemical processes (e.g., transcription, protein stability and/or protein localization) within living cells.