Calcium acts as a signal and transmits information in all eukaryotes. Encoding machinery consisting of calcium channels, stores, buffers and pumps can generate a variety of calcium transients in response to external stimuli, thus shaping the calcium signature. Mechanisms for the transmission of calcium signals have been described and a large repertoire of calcium binding proteins exist that can decode calcium signatures into specific responses. Whilst straightforward in concept, mysteries remain in exactly how such information processing is biochemically implemented. Novel developments in imaging technology and genetically encoded sensors (such as calcium indicators), in particular for multi-signal detection, are delivering exciting new insights into intra- and intercellular calcium signaling. Here, we review recent advances on characterising the encoding, transmission and decoding mechanisms, with a focus on long distance calcium signaling. We present technological advances and computational frameworks for studying the specificity of calcium signaling, highlighting current gaps in our understanding and suggesting techniques and approaches for unravelling the underlying mechanisms.