**1. Introduction**

Implantation requires a complex crosstalk between the endometrium and the blastocyst and is highly regulated by a variety of factors, such as soluble growth factors, hormones, prostaglandins, adhesion molecules, and the extracellular matrix (ECM) [1–5]. These factors, produced by the receptive endometrium in response to the presence of the blastocyst and vice versa, are able to synchronize the development of the embryo to the blastocyst stage and the differentiation of the uterus to the receptive state [6,7]. This complex network of signaling accounts for implantation being one of the major limiting steps in mammalian reproduction. Indeed, the implantation rate in humans is about 30% per cycle [8,9]. Alterations of these signaling pathways may result in pathological conditions leading to infertility.

The WHO has designated infertility as "a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse" [10,11]. Infertility is one of the main health issues in all societies worldwide, with a prevalence of 3.5–16.7% in developed countries and 6.9–9.3% in developing countries [12,13] and may be a consequence of low embryo quality, male problems, or female dysfunctions. Female fertility problems account for 20–35% of infertility cases and may derive from a wide variety of causes such as age, anatomical, endocrine and immunological problems, and several pathological conditions affecting the endometrium [14–19]. These conditions may lead to defects in blastocyst implantation in the maternal uterus, resulting in implantation failure, a common cause of impaired fertility [20]. The term "implantation failure" actually implies a series of conditions in which the embryo does not implant in the maternal endometrium after both spontaneous and in vitro fertilization (IVF) [21]. A condition in which implantation failure occurs after the transfer of three or more good quality embryos is defined recurrent implantation failure (RIF) and it is only applicable to assisted reproductive technology (ART) [21,22]. According to ASRM and ESHRE definitions, RIF is considered a distinct pathological condition from recurrent pregnancy loss [21,23,24].

The present review describes and discusses the molecular mechanisms underlying the implantation process, focusing on factors implicated in the complex blastocyst–endometrium crosstalk, which are crucial for successful implantation. Further research for new factors involved in the dialogue between the blastocyst and the endometrium would allow to reduce the current rates of implantation failure, allowing many couples with infertility problems to reach a successful pregnancy.
