Phosphate and sulfate are two macro-elements essential for plant growth and development. Both elements play a central role in numerous aspects of plant metabolism and their deficiencies have profound effects on the transcriptome as well as on numerous metabolic pathways. The research emphasis so far has been on elucidating the molecular physiology of these individual nutritive elements. Recent data proved the existence of complex connections between the various regulatory layers of the homeostasis of these elements, but the molecular bases and biological significance of such interconnections remains poorly understood. This review provides an update on recent advances to identify the components involved in phosphate and sulfate homeostasis crosstalk. In light of this case study, developing a comprehensive understanding of the coordination of the ion homeostasis and identifying genes which can be used as good molecular markers for monitoring the “integrative ionic status” of plants is not only of great scientific interest, but also crucial for biotechnological and agronomic applications.