The integration of drugs into nanocarriers favorably altered their pharmacodynamics and pharmacokinetics compared to free drugs, and increased their therapeutic index. However, selective cellular internalization in diseased tissues rather than normal tissues still presents a formidable challenge. In this chapter I will cover solutions involving environment-responsive cell-penetrating peptides (CPPs). I will discuss properties of CPPs as universal cellular uptake enhancers, and the modifications imparted to CPP-modified nanocarriers to confine CPP activation to diseased tissues.