Poor delivery efficiency continues to hamper the effectiveness of cancer therapeutics engineered to destroy solid tumors using different strategies such as nanocarriers, targeting agents, and matching treatments to specific genetic mutations. All contemporary systemic anti-cancer agents are dependent upon passive transvascular mechanisms for their delivery into solid tumors. The therapeutic efficacies of our current drug arsenal could be significantly improved with an active delivery strategy. Here, we discuss how drug delivery and therapeutic efficacy are greatly hindered by barriers presented by the vascular endothelial cell layer and by the aberrant nature of tumor blood vessels in general. We describe mechanisms by which molecules cross endothelial cell (EC) barriers in normal tissues and in solid tumors, including paracellular and transcellular pathways that enable passive or active transport. We also discuss specific obstacles to drug delivery that make solid tumors difficult to treat, as well strategies to overcome them and enhance drug penetration. Finally, we describe the caveolae pumping system, a promising active transport alternative to passive drug delivery across the endothelial cell barrier. Each strategy requires further testing to define its therapeutic applicability and clinical utilities.