Most of the previous studies in last three decades report evidence of interactions between the different phytochemicals and the proteins involved in signal transduction pathways using in silico, in vitro, ex vivo, and in vivo analyses. However, extrapolation of these findings for clinical purposes has not been that fruitful. The efficacy of the phytochemicals in vivo studies is limited by parameters such as solubility, metabolic degradation, excretion, etc. Various approaches have now been devised to circumvent these limitations. Recently, chemical modification of the phytochemicals are demonstrated to reduce some of the limitations and improve their efficacy. Similar to traditional medicines several combinatorial phytochemical formulations have shown to be more efficient. Further, phytochemicals have been reported to be even more efficient in the form of nanoparticles. However, systematic evaluation of their efficacy, mode of action in pathway modulation, usage and associated challenges is required to be done. The present review begins with basic understanding of how signaling cascades regulate cellular response and the consequences of their dysregulation further summarizing the developments and problems associated with the dietary phytochemicals and also discuss recent approaches in strengthening these compounds in pharmacological applications. Only context relevant studies have been reviewed. Considering the limitations and scope of the article, authors do not claim inclusion of all the early and recent studies.