Development, regeneration, and even day-to-day physiology require plant and animal cells to make decisions based on their locations. The principles by which cells may do this are deceptively straightforward. But when reliability needs to be high--as often occurs during development--successful strategies tend to be anything but simple. Increasingly, the challenge facing biologists is to relate the diverse diffusible molecules, control circuits, and gene regulatory networks that help cells know where they are to the varied, sometimes stringent, constraints imposed by the need for real-world precision and accuracy.

Why is the sky blue? Any scientist will answer this question with a statement of mechanism: Atmospheric gas scatters some wavelengths of light more than others. To answer with a statement of purpose—e.g., to say the sky is blue in order to make people happy—would not cross the scientific mind. Yet in biology we often pose “why” questions in which it is purpose, not mechanism,that interests us. The question “Why does the eye have a lens?” most often calls for the answer that the lens is there to focus light rays, and only rarely for the answer that the lens is there because lens cells are induced by the retina from overlying ectoderm.

The theory that the spatial organization of cell fate is orchestrated by gradients of diffusing molecules was a major contribution to 20th century developmental biology. Although the existence of morphogens is no longer in doubt, studies on the formation and function of their gradients have yielded far more puzzles than answers. On close inspection, every morphogen gradient seems to use a rich array of regulatory mechanisms, suggesting that the tasks carried out by such systems are far more extensive than previously thought.

Neural cells make and break many contacts during their lifetime. The processes of neuroblast migration, axon elongation and guidance, synaptogenesis, myelination and synaptic rearrangement all require the selective formation and elimination of cell-cell and cell-substratum associations.

Developmental biology, regenerative medicine and cancer biology are increasingly occupied with the molecular characterization of stem cells. Yet recent work adds to a growing body of literature suggesting that 'stemness' cannot be reduced to the molecular features of cell types, and is instead an emergent property of cell lineages under feedback control.

Sulfated glycosaminoglycans bind to a wide variety of proteins, and in so doing have important roles in diverse biological processes. Selective mimics or inhibitors of protein-glycosaminoglycan interactions could have broad application in biology and medicine.

Systems biology seeks not only to discover the machinery of life but to understand how such machinery is used for control, i.e., for regulation that achieves or maintains a desired, useful end. This sort of goal-directed, engineering-centered approach also has deep historical roots in developmental biology. Not surprisingly, developmental biology is currently enjoying an influx of ideas and methods from systems biology. This Review highlights current efforts to elucidate design principles underlying the engineering objectives of robustness, precision, and scaling as they relate to the developmental control of growth and pattern formation. Examples from vertebrate and invertebrate development are used to illustrate general lessons, including the value of integral feedback in achieving set-point control; the usefulness of self-organizing behavior; the importance of recognizing and appropriately handling noise; and the absence of "free lunch." By illuminating such principles, systems biology is helping to create a functional framework within which to make sense of the mechanistic complexity of organismal development.