Drug delivery has made tremendous advances in the last decade. Targeted therapies are increasingly common, with intracellular delivery highly impactful and sought after. Intracellular drug delivery systems have limitations due to imprecise and non-targeted release profiles. One way this can be addressed is through using stimuli-responsive soft nanoparticles, which contain materials with an organic backbone such as lipids and polymers. The choice of biomaterial is essential for soft nanoparticles to be responsive to internal or external stimuli. The nanoparticle must retain its integrity and payload in non-targeted physiological conditions while responding to particular intracellular environments where payload release is desired. Multiple internal and external factors could stimulate the intracellular release of drugs from nanoparticles. Internal stimuli include pH, oxidation, and enzymes, while external stimuli include ultrasound, light, electricity, and magnetic fields. Stimulatory responsive soft nanoparticulate systems specifically utilized to modulate intracellular delivery of drugs are explored in this review.