The clinical use of cannabinoids is currently a topic of interest not exclusively, but most importantly, concerning different areas of pain therapy. One of the major obstacles in developing clinically acceptable compounds is the cannabimimetic side-effect profile of delta-9-tetrahydrocannabinol (THC) and other cannabinoids. This article gives a brief overview of the endocannabinoid system, its components and functions and explains the current approaches to avoiding cannabimimetic side effects by separating them from the therapeutic effects. One of these approaches is the addition of cannabidiol (CBD) as well as the use of preparations suitable for oromucosal application. Also cannabinoids, which primarily stimulate peripheral cannabinoid-1 (CB1) receptors or selectively cannabinoid-2 (CB2) receptors, can further separate analgesic activity from cannabimimetic activity. Local or topical modes of application are another attempt aiming in the same direction. Modulating the endogenous cannabinoid tone (via the inhibition of endocannabinoid-metabolising enzymes) is another strategy. The combination of THC in low, non-psychoactive doses with opioids has a synergistic effect and reduces opioid tolerance effects. Available data from these approaches are summarised and their more and less promising aspects are discussed.