In the past decade, the tendency to move from a global, one-size-fits-all treatment philosophy to personalized medicine is based, in part, on the nuanced differences and sub-classifications of disease states. Our knowledge of these varied states stems from not only the ability to diagnose, classify, and perform experiments on cell populations as a whole, but also from new technologies that allow interrogation of cell populations at the individual cell level. Such departures from conventional thinking are driven by the recognition that clonal cell populations have numerous activities that manifest as significant levels of non-genetic heterogeneity. Clonal populations by definition originate from a single genetic origin so are regarded as having a high level of homogeneity as compared to genetically distinct cell populations. However, analysis at the single cell level has revealed a different phenomenon; cells and organisms require an inherent level of non-genetic heterogeneity to function properly, and in some cases, to survive. The growing understanding of this occurrence has lead to the development of methods to monitor, analyze, and better characterize the heterogeneity in cell populations. Following the trend of DNA- and protein microarrays, platforms capable of simultaneously monitoring each cell in a population have been developed. These cellular microarray platforms and other related formats allow for continuous monitoring of single live cells and simultaneously generate individual cell and average population data that are more descriptive and information-rich than traditional bulk methods. These technological advances have helped develop a better understanding of the intricacies associated with biological processes and afforded greater insight into complex biological systems. The associated instruments, techniques, and reagents now allow for highly multiplexed analyses, which enable multiple cellular activities, processes, or pathways to be monitored simultaneously. This critical review will discuss the paradigm shift associated with cellular heterogeneity, speak to the key developments that have lead to our better understanding of systems biology, and detail the future directions of the discipline (281 references).