The post-genomic era has produced a variety of new investigation technologies, techniques and approaches that may offer exciting insights into many long-standing questions of scientific research. The microtubule cytoskeleton is a highly conserved system that shows a high degree of internal complexity, is known to be integral to many cell systems and functions on a fundamental level. After decades of study, much is still unknown about microtubules in vivo from the control of dynamics in living cells to their responses to environmental changes and responses to other cellular processes. In the present article, we examine some outstanding questions in the microtubule field and propose a combination of emerging interdisciplinary approaches, i.e. high-throughput functional genomics techniques, quantitative and super-resolution microscopy, and in silico modelling, that could shed light on the systemic regulation of microtubules in cells by networks of regulatory factors. We propose that such an integrative approach is key to elucidate the function of the microtubule cytoskeleton as a complete responsive integral biological system.