Adenovirus-based vectors comprise the most frequently used vector type in clinical studies to date. Both intense lab research and insights from the clinical trials reveal the importance of a comprehensive understanding of vector–host interactions. Especially for systemic intravenous adenovirus vector delivery, it is paramount to develop safe and efficacious vectors. Very early vector–host interactions that take place in blood long before the first cell is being transduced are phenomena triggered by the surface, shape, and size of the adenovirus vector particles. Not surprisingly, a multitude of different technologies ranging from genetics to chemistry has been developed to alter the adenovirus vector surface. In this review, we discuss the most important technologies and evaluate them for their suitability to overcome hurdles imposed by early vector–host interactions.