Rapid advances in genomics discovery tools and a growing realization of microRNAs implication in intercellular communication have led to a proliferation of studies of circulating microRNA sorting and regulation across cells and different species. Although sometimes, reaching controversial scientific discoveries and conclusions, these studies have yielded new insights in the functional roles of circulating microRNA and a plethora of analytical methods and tools. Here, we consider this body of work in light of key computational principles underpinning discovery of circulating microRNAs in terms of their sorting and targeting, with the goal of providing practical guidance for applications that is focused on the design and analysis of circulating microRNAs and their context-dependent regulation. We survey a broad range of informatics methods and tools that are available to the researcher, discuss their key features, applications and various unsolved problems and close this review with prospects and broader implication of this field.