The brain-cell microenvironment plays an important role in brain function and includes neurons and glial cells, the extracellular space (ECS) between them, and the intracellular spaces (ICS) within them. The major ions, Na+, K+, and CI-, have dynamics on a sub-cellular scale that account for ion movements in the ECS and ICS and across cell membranes. These ions have significant effects on cell membrane electrical activity. Although we know a lot about the many different mechanisms that are operative in the brain at the cellular level, we know very little about how they conspire to yield a normal functioning brain. We can gain new information about how the normal brain functions by studying extreme phenomena, e.g., spreading cortical depression (SD), which is a slow wave phenomenon (1-15 mm/min) that has been observed during experiments in a variety of brain structures in various animals. Spreading depression has been recognized as a pathological brain phenomenon for 60 years and has been investigated with extensive experimental and theoretical studies. In spite of these, we know very little about how SD is instigated and propagated. Also, there is a possible link of SD with disease. In this talk, I will describe spreading depression and indicate several mechanisms that are believed to be important in modelling SD. These mechanisms include ion diffusion, the spatial buffer mechanism, osmotic effects, neurotransmitter substances, gap junctions, and synaptic connections. The long-term objective of these studies is to develop a realistic physiological model for spreading depression.