I try to approximate the natural circadian rhythm for cortisol which peaks just before dawn, declines throughout the day and is lowest just after midnight. I take my largest cortef dose when I awaken in the AM and a smaller dose in mid afternoon. For an explanation and graphs of the cortisol/aldosterone circadian cycle go to: http://www.cbt.virginia.edu/tutorial/HUMANCLOCKP3.html I don't think this is critical, it's just closer to the way my pituitary gland probably signals my adrenals to try to make cortisol.