Delivery of therapeutic molecules at the right time, place and at the correct dosage is critical to improve the effectiveness of therapeutic regimens. Barriers in the body, normally needed to maintain function, often impede delivery of therapeutic payloads to their target areas. Designing innovative solutions to circumvent these environmental factors, and ensure the timely delivery of therapeutic doses, is an essential element in improving human health. Here we highlight recent studies that focus on bypassing different barriers crucial for improving therapeutic delivery, by temporarily modifying the in vivo microenvironment, re-designing therapeutic carrier vehicles to improve control characteristics and on-demand delivery, and developing convenience-based strategies to improve patient compliance and access to therapeutics.