Present-day cellular systems biology is producing data on an unprecedented scale. This field has generated a renewed interest in the holistic, "system" character of cell structure-and-function. Underlying the data deluge, however, there is a clear and present need for a historical foundation. The origin of the "system" view of the cell dates to the birth of the protoplasm concept. The 150-year history of the role of "protoplasm" in cell biology is traced. It is found that the "protoplasmic theory," not the "cell theory," was the key 19th-century construct that drove the study of the structure-and-function of living cells and set the course for the development of modern cell biology. The evolution of the "protoplasm" picture into the 20th century is examined by looking at controversial issues along the way and culminating in the current views on the role of cytological organization in cellular activities. The relevance of the "protoplasmic theory" to 21st-century cellular systems biology is considered.